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AU2022413759A1 - Benzoate salt of 5-methoxy-n,n-dimethyltryptamine - Google Patents

Benzoate salt of 5-methoxy-n,n-dimethyltryptamine Download PDF

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AU2022413759A1
AU2022413759A1 AU2022413759A AU2022413759A AU2022413759A1 AU 2022413759 A1 AU2022413759 A1 AU 2022413759A1 AU 2022413759 A AU2022413759 A AU 2022413759A AU 2022413759 A AU2022413759 A AU 2022413759A AU 2022413759 A1 AU2022413759 A1 AU 2022413759A1
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Australia
Prior art keywords
meo
dmt
benzoate
treatment
pattern
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AU2022413759A
Inventor
Cosmo FEILDING-MELLEN
Jason Gray
Timothy Mason
Cosima Agnes RUDD GRETTON
Frank Wiegand
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Beckley Psytech Ltd
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Beckley Psytech Ltd
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Priority claimed from GBGB2118005.4A external-priority patent/GB202118005D0/en
Priority claimed from GBGB2118007.0A external-priority patent/GB202118007D0/en
Priority claimed from GBGB2118006.2A external-priority patent/GB202118006D0/en
Priority claimed from GBGB2118008.8A external-priority patent/GB202118008D0/en
Priority claimed from GBGB2118011.2A external-priority patent/GB202118011D0/en
Priority claimed from GBGB2118095.5A external-priority patent/GB202118095D0/en
Priority claimed from GBGB2118099.7A external-priority patent/GB202118099D0/en
Priority claimed from GBGB2118156.5A external-priority patent/GB202118156D0/en
Priority claimed from GBGB2212113.1A external-priority patent/GB202212113D0/en
Priority claimed from GBGB2212117.2A external-priority patent/GB202212117D0/en
Application filed by Beckley Psytech Ltd filed Critical Beckley Psytech Ltd
Publication of AU2022413759A1 publication Critical patent/AU2022413759A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A method of synthesizing the benzoate salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with a base, prior to the addition of benzoic acid.

Description

Benzoate salt of 5-Methoxy-N,N-dimethyltryptamine
Field of the invention
This invention relates to the benzoate salt of 5-methoxy-N,N-dimethyltryptamine, methods of synthesis, formulations, applications, and uses of the same.
Background of the invention
5-methoxy-N,N-dimethyltryptamine benzoate (hereafter 5-MeO-DMT benzoate) is the benzoate salt of the pharmacologically active compound of the tryptamine class, 5-MeO-DMT, and has the following chemical structure:
5-MeO-DMT is a psychoactive/psychedelic substance found in nature and is believed to act mainly through serotonin receptors. It is also believed to have a high affinity for the 5-HT2 and 5-HTIA subtypes, and/or inhibits monoamine reuptake.
There remains a need in the art for improved methods of synthesis, formulations, applications, uses of 5-MeO-DMT benzoate.
Summary of the invention
Herein disclosed, there is provided a method for the synthesis of 5-MeO-DMT benzoate. Herein disclosed, there is provided a method for the synthesis of 5-MeO-DMT benzoate via the hydrochloride salt.
In an aspect of the invention there is provided a method of synthesizing the benzoate salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with a base, prior to the addition of benzoic acid.
Advantageously, making the benzoate salt via the HCI salt improves the quality of the benzoate salt, for example as compared to making the benzoate salt directly from the free base. Base washing the salt improves the quality of the resultant benzoate salt.
In an embodiment, the benzoate salt is crystalline. In an embodiment, the benzoate salt is crystalline, as described subsequently herein below. In an embodiment, the benzoate salt is crystalline and conforms to Pattern A, B, C, D, E, F, G or H. In an embodiment, the benzoate salt is crystalline Pattern A. In an embodiment, the method comprises the step of suspending the hydrochloride salt in a suspending organic solvent; wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the benzoic acid is in solution in an organic solvent; wherein optionally the organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the benzoic acid and the hydrochloride salt precursor (or resultant free base) are present in substantially equal molar amounts.
In an embodiment, the reaction with the benzoic acid takes place at an elevated temperature, optionally at a temperature between 40-65, 45-60, 50-55°C, or at/near the boiling point of the resultant reaction mixture. In an embodiment, the reaction with the benzoic acid takes place at an elevated temperature, and the resultant reaction mixture is allowed to cool to room temperature or lower, is allowed to cool to below 10°C, is allowed to cool to below 5°C, or is allowed to cool to between 5 and 0°C. In an embodiment, the benzoate salt is filtered from the resultant reaction mixture. In an embodiment, the filtered benzoate salt is washed with a washing organic solvent; wherein optionally the washing organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
In an embodiment, the benzoate salt is washed with cooled washing organic solvent, optionally the washing organic solvent is cooled to below room temperature, is cooled to below 10°C, is cooled to below 5°C, or cooled to between 5 and 0°C. In an embodiment, the filtered benzoate salt is dried under vacuum. In an embodiment, the hydrochloride salt is base-treated with an aqueous basic solution, prior to the addition of benzoic acid. In an embodiment, the hydrochloride salt is base-treated prior to the reaction with benzoic acid, optionally the hydrochloride salt is base- treated with an aqueous basic solution. In an embodiment, the hydrochloride salt is not isolated prior to the base washing.
In an embodiment, the basic solution comprises an alkoxide, optionally the basic solution comprises sodium hydroxide, further optionally the basic solution is 5% aqueous sodium hydroxide. In an embodiment, the hydrochloride salt is suspended in the suspending organic solvent prior to being base-treated, wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the resultant based-treated reaction is partitioned with an extracting organic solvent to give an extract comprising the base-conditioned hydrochloride salt; wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the suspending organic solvent is isopropyl acetate (IPAc). In an embodiment, the organic solvent is IPAc. In an embodiment, the washing organic solvent is IPAc. In an embodiment, the extracting organic solvent is IPAc. In an embodiment, the organic phase is washed with water. In an embodiment, the extract is reduced under vacuum to give a concentrate, optionally the extract is concentrated to approximately 8 volumes. In an embodiment, the extract is azeotropically dried with one or more batches of fresh extracting organic solvent, optionally the extracting organic solvent is IPAc.
In an embodiment, the method comprises the steps of: combining 5-MeO-DMT hydrochloride salt and an organic solvent; optionally the organic solvent is IPAc adding a basic solution to the combined 5-MeO-DMT hydrochloride salt and organic solvent; optionally the basic solution is aqueous 5% NaOH;
Partitioning; washing the resulting organic phase with water; drying the solvent; optionally azeotropically with IPAc concentrating under vacuum; adjusting the solvent temperature to between about 50-55°C; adding a solution of benzoic acid in further organic solvent; optionally the further organic solvent is IPAc adjusting the temperature to between about 0-5°C; filtering and washing with cold solvent; optionally the cold solvent is IPAc drying under vacuum to obtain the 5-MeO-DMT benzoate salt as a crystalline solid.
In an embodiment, the crystalline 5-MeO-DMT benzoate produced is characterised by one or more of: peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20; and/or endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C.; and/or enthalpy in a DSC thermograph of between -130 and -140J/g; and/or onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
In an embodiment, there is provided 5-MeO-DMT benzoate produced by the previously or subsequently described methods. In an embodiment, the method of synthesis is a method of large scale synthesis. In an embodiment, the method of synthesis is a method of synthesis of >100g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >200g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >300g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >400g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >500g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >100g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >200g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >300g of 5- MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >400g of 5-MeO- DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >500g of 5-MeO-DMT benzoate.
In an embodiment, the method of synthesis is a method of synthesis of an amorphous dry powder of 5-MeO-DMT benzoate. In an embodiment, there is provided an amorphous dry powder of 5-MeO-DMT benzoate. In an embodiment, there is provided a method of synthesis of 5-MeO-DMT benzoate wherein the 5-MeO-DMT benzoate is synthesised by reacting 5-MeO-DMT hydrochloride with a suitable solvent and benzoic acid. Use of 5-MeO-DMT benzoate salt, produced by any of the methods described herein, in a method of medical treatment.
In an embodiment, there is provided a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid. In an embodiment, there is provided a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid in an organic solvent. In an embodiment, there is provided a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid in an organic solvent, wherein the resultant organic acid salt of 5-MeO-DMT is less soluble than the HCI salt of 5-MeO-DMT in the organic solvent.
In an embodiment, there is provided a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid in an organic solvent, wherein the HCI salt is placed in the organic solvent and the resultant organic acid salt of 5-MeO-DMT is less soluble in the organic solvent than the HCI salt of 5-MeO-DMT, and wherein the organic acid salt of 5-MeO-DMT remains in solution when the organic solvent is at elevated temperature, but falls out of solution when the reaction mixture is cooled. In an embodiment, there is provided a method of synthesizing an organic acid salt of 5-MeO-DMT, wherein the HCI salt is base-treated prior to the reaction with the organic acid, optionally the hydrochloride salt is basetreated with an aqueous basic solution, further optionally base-treated with aqueous NaOH (e.g. 5% NaOH). In an embodiment, the organic acid is selected from any of the known organic acids. In an embodiment, the organic acid is selected from: lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, benzoic acid or tartaric acid. In an embodiment, the organic acid is benzoic acid. In an embodiment, there is provided a method of recrystallising the benzoate salt of 5-MeO-DMT from an organic solvent, wherein the solvent is selected from one or more of an alcohol, ester, an acetate and/or an acetate alcohol, ester, and optionally IPAc or IPA. In an embodiment, there is provided a method of purifying the HCI salt of 5-MeO-DMT, comprising the step of basetreating the HCI salt, optionally the hydrochloride salt is base-treated with an aqueous basic solution, further optionally base-treated with aqueous NaOH (e.g. 5% NaOH). In an embodiment, the 5-MeO-DMT salt contains no more than 1% of the hydroxyl impurity, shown below:
In an embodiment, the 5-MeO-DMT salt contains no more than 2% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT salt contains no more than 3% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT salt contains no more than 4% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT salt contains no more than 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 1% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 2% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 3% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 4% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 1% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 2% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 3% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 4% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 1% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 2% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 3% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 4% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 5% of any impurity.
In an embodiment, the 5-MeO-DMT benzoate synthesised by the methods of the invention is substantially free of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate synthesised by the methods of the invention contain no more than 1%, no more than 2%, no more than 3%, no more than 4% and/or no more than 5% of the hydroxyl impurity. In an embodiment, purity of the 5-MeO-DMT is determined by HPLC or RP-HPLC. In an embodiment, the 5-MeO-DMT has chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by HPLC. In an embodiment, the 5-MeO-DMT has chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by RP-HPLC. In an embodiment, there is no single impurity of greater than 1% by HPLC or RP-HPLC. A method of synthesizing the benzoate salt of 5-MeO-DMT according to any one of the aspects or embodiments herein disclosed, wherein the hydrochloride salt is instead any non-benzoate salt, optionally the non-benzoate salt is a hydro-halide salt (e.g. the resultant counter ion is fluoride, chloride, bromide, iodide, fumarate, succinate, oxalate, acetate, citrate, triflate, phosphate, tartrate, benzenesulfonate, tosylate, adipate, glycolate, ketoglutarate, malate, saccharinate).
Herein disclosed, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). In an embodiment, the salt anion is an aryl carboxylate. In an embodiment, the aryl carboxylate is substituted with one to three R groups.
In an embodiment, the one or more R groups are independently selected from: alkynyl, carbonyl, aldehyde, haloformyl, alkyl, halide, hydroxy, alkoxy, carbonate ester, carboxylate, carboxyl, carboalkoxy, methoxy, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxylic anhydride, carboxamide, secondary, tertiary or quaternary amine, primary or secondary ketimine, primary or secondary aldimine, imide, azide, azo, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro, nitroso, oxime, pyridyl, carbamate, sulfhydryl, sulfide, disulfide, sulfinyl, sulfonyl, sulfino, sulfo, thiocyanate, isothiocyanate, carbonothioyl, carbothioic S-acid, carbothioic O-acid, thiolester, thionoester, carbodithioic acid, carbodithio, phosphino, phosphono, phosphate, borono, boronate, borino or borinate.
In an embodiment, the one or more R groups are independently selected from: Ci - Cs alkyl, Ci - Cs alkoxy, Ci - Ce alkenyl or Ci - Ce alkynyl, and where each of these may be optionally substituted with one to three R groups as previously described.
In an aspect of the invention, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine.
The invention provides for improved formulations and uses of 5-MeO-DMT salts. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.05mg to lOOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of O.lmg to 50mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5mg to 25mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5mg to lOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of lmg to lOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of lmg to 8mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 3mg to 15mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.005mg to lOOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of O.OOlmg to lOOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.0005mg to lOOmg. The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
In an embodiment, the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated. In an embodiment, the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form. In an embodiment, the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
In an embodiment, the powder comprises particles, the particles having a median diameter of less than 2000pm, 1000pm, 500pm, 250pm, 100pm, 50pm, or 1pm. In an embodiment, the powder comprises particles, the particles having a median diameter of less than 15, 14, 13, 12, 11, or 10pm. In an embodiment, the powder comprises particles, the particles having a median diameter of less than 9pm. In an embodiment, the powder comprises particles, the particles having a median diameter of greater than 500pm, 250pm, 100pm, 50pm, 1pm or 0.5pm. In an embodiment, the powder comprises particles, and wherein the powder has a particle size distribution of dl0=20- 60pm, and/or d50=80-120pm, and/or d90=130-300pm.
The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet. In an embodiment, the 5-MeO-DMT salt is amorphous or crystalline. In an embodiment, the 5-MeO-DMT salt is a benzoate, fumarate, citrate, acetate, succinate, halide, phosphate, tartrate, benzenesulfonate, tosylate, adipate, glycolate, ketoglutarate, malate, saccharinate, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.
In an embodiment, the 5-MeO-DMT salt is formulated into a composition for mucosal delivery. In an embodiment, the 5-MeO-DMT salt is a benzoate salt. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern A as characterised by an XRPD diffractogram. In an embodiment, the 5-MeO-DMT benzoate is characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, 5-MeO-DMT benzoate is characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 6 or Figure 7. In an embodiment, the 5-MeO-DMT benzoate is characterised by bands at ca. 3130, 1540, 1460, 1160 and 690 cm-1 in a fourier-transform infrared spectroscopy (FTIR) spectra. In an embodiment, the 5-MeO-DMT benzoate is characterised by a FTIR spectra for lot FP2 as substantially illustrated in Figure 93. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B as characterised by peaks in an XRPD diffractogram between 18.5 and 20° 20±O.1°20. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B as substantially illustrated by the XRPD diffractogram for lots Pl, R1 and QI as substantially illustrated in Figure 24.
In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B as substantially illustrated by the XRPD diffractogram for lot R2 as substantially illustrated in Figure 28. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B as substantially illustrated by the XRPD diffractogram for lots Al and Bl as substantially illustrated in Figures 38 or 39. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern B form as characterised by FTIR spectra for lot C2 as substantially illustrated in Figure 93. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern C form as characterised by a minor broad endotherm with a peak temperature of 108°C in a DSC thermograph. In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern C as characterised by a DSC thermograph as substantially illustrated in Figure 65. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern C form as characterised by a DSC thermograph as substantially illustrated in Figure 66. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern C by XRPD. In an embodiment, the 5- MeO-DMT benzoate conforms to Pattern C as characterised by a peak in an XRPD diffractogram at 10.3° 20±O.1°20. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern C as substantially illustrated by the XRPD diffractogram for lot Al as substantially illustrated in Figure 68. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern C form as characterised by FTIR spectra for lot Cl as substantially illustrated in Figure 93. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern D by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern D as substantially illustrated by the XRPD diffractogram in Figure 73 or Figure 74. In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern D as characterised by an endothermic event in a DSC thermograph at 118°C. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern D form as characterised by an endothermic event in a DSC thermograph at 118.58°C.
In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern E by XRPD. In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern E as substantially illustrated by the XRPD diffractogram for lot D in Figure 77 or Figure 78. In an embodiment, the 5-MeO-DMT corresponds to the Pattern E form as characterised by a major bimodal endothermic event with peak temperatures of 110.31°C and 113.13°C in a DSC thermograph. In an embodiment, the 5-MeO-DMT corresponds to Pattern E as characterised by a minor endothermic event with a peak temperature of 119.09°C in a DSC thermograph. In an embodiment, the 5-MeO-DMT corresponds to the Pattern E form as characterised by a DSC thermograph as substantially illustrated in Figure 79.
In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern E as substantially illustrated by the XRPD diffractogram in Figure 80. In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern F by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern F as characterised by an XRPD diffractogram for lot F (rerun) as substantially illustrated in Figure 84. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern F as characterised by an XRPD diffractogram for lot F (rerun) as substantially illustrated in Figure 85. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern F as characterised by an XRPD diffractogram for lot F (rerun) as substantially illustrated in Figure 89. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern F form as characterised by endothermic events at 90°C, 106°C and 180°C in a DSC thermograph. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern F form as characterised by endothermic events at 90.50°C, 106.65°C and 180.35°C in a DSC thermograph.
In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern G by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern G, as characterised by an XRPD diffractogram for lot K as substantially illustrated in Figure 87. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern G form, as characterised by an endothermic event in a DSC thermograph of 119.61°C. In an embodiment, the composition comprises 5-MeO-DMT benzoate which conforms to a mixture of two or more of Patterns A to G by XRPD.
For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So lOOmg dosage amount of 5-MeO-DMT corresponds to 117mg of the hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt (i.e. 218.3 g/mol for the free base as compared to 254.8 g/mol for the salt). Similarly, for the deuterated or triturated version of 5-MeO-DMT (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties. In an embodiment, the composition comprises one or more pharmaceutically acceptable carriers or excipients. In an embodiment, the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
In an embodiment, the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N- trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment, the composition disclosed herein is for use as a medicament. In an embodiment, the composition disclosed herein is for use in a method of treatment of a human or animal subject by therapy.
In an embodiment, the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
Treatment of the above conditions may be beneficially improved by taking the invention.
In an embodiment, the method of treatment is a method of treatment of alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepine abuse or dependence related disorders, and/or opioid-related disorders. In an embodiment, the method of treatment is a method of treatment of tobacco addiction. In an embodiment, the method is a method of reducing tobacco use. In an embodiment, the method of treatment is a method of treatment of nicotine addiction. In an embodiment, the method is a method of reducing nicotine use.
In an embodiment, the method of treatment is a method of treating alcohol abuse and/or addiction. In an embodiment, the method of treatment is a method of reducing alcohol use.
In an embodiment, the method of treatment is a method of treating or preventing heavy drug use.
In an embodiment, the method of treatment is a method of treating or preventing heavy drug use, including, but not limited to, alcohol, tobacco, nicotine, cocaine, methamphetamine, other stimulants, phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers, hypnotics, and opiates. It will be appreciated by one of ordinary skill in the art that heavy use or abuse of a substance does not necessarily mean the subject is dependent on the substance.
In an embodiment, the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety. In an embodiment, the composition is administered one or more times a year. In an embodiment, the composition is administered one or more times a month. In an embodiment, the composition is administered one or more times a week. In an embodiment, the composition is administered one or more times a day. In an embodiment, the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment, the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment, the further active agent is a psychedelic compound, optionally a tryptamine. In an embodiment, the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof. In an embodiment, the further active agent is an antidepressant compound. In an embodiment, the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
In an embodiment, the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen/Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4), Triiodothyronine (T3).
In an embodiment, the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).
In an embodiment, the complementary treatment is psychotherapy. In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5- MeO-DMT for use in a method of treatment of treatment resistant depression (TRD). In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-MeO-DMT for use in a method of treatment of depression. In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5- MeO-DMT for use in a method of treatment of PTSD. In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-MeO-DMT for use in a method of treatment of addiction/substance misuse disorders. In an embodiment, there is provided a nasal inhalation composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-MeO-DMT for use in a method of treatment of treatment resistant depression.
Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day. For the sake of brevity only, various forms of the 5-MeO- DMT benzoate salt may be referred to herein below as 'Pattern wherein the # refers to the corresponding XRPD pattern obtained for that form. For example, 'Pattern A' may be used as an abbreviation to refer to the form of 5- MeO-DMT benzoate salt giving rise to the Pattern A by XRPD. Likewise, 'Pattern B' may be used as an abbreviation to refer to the form of 5-MeO-DMT benzoate salt giving rise to the Pattern B by XRPD, and so on.
The present invention will now be further described with reference to the following, and the accompanying drawings, of which:
Brief description of the drawings
Figure 1 is a schematic route for the synthesis of 5-MeO-DMT.
Figure 2 is a further schematic route for the synthesis of 5-MeO-DMT.
Figure 3 is a schematic route for the preparation of a powder form of 5-MeO-DMT.
Figure 4 is an overview of the slug mucosal irritation (SMI) test. (A) First 15 minute contact period between slug and test item. (B) Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour. (C) Second 15 minute contact period between slug and test item. (D) Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour. (E) Third 15 minute contact period between slug and test item.
Figure 5 is a graph showing that the benzoate salt of 5-MeO-DMT has higher permeation compared with the hydrochloride salt, as per the experiment detailed in Example 9.
Figure 6 shows an XRPD diffractogram of 5-MeO-DMT benzoate prior to particle size reduction.
Figure 7 shows an XRPD diffractogram of 5-MeO-DMT benzoate following particle size reduction.
Figure 8 shows the XRPD diffractograms of Figures 6 and 7 overlaid on one another.
Figure 9 shows a DSC thermograph of 5-MeO-DMT benzoate.
Figure 10 shows a TGA thermograph of 5-MeO-DMT benzoate.
Figure 11 shows a combined TGA/DSC thermograph of 5-MeO-DMT benzoate.
Figure 12 shows a DVS isotherm of 5-MeO-DMT benzoate.
Figure 12 shows a Dynamic Vapour Sorption (DVS) isotherm for 5-MeO-DMT benzoate.
Figure 13 shows an optical micrograph of 5-MeO-DMT benzoate salt (A) and dark field (B) at x4 magnification.
Figure 14 shows two further optical micrographs of 5-MeO-DMT benzoate salt (A) and (B) at x4 magnification.
Figure 15 shows optical micrographs of 5-MeO-DMT benzoate salt (A) and (B) at xlO magnification.
Figure 16 shows further optical micrographs of 5-MeO-DMT benzoate salt (A) and (B) at lOx magnification.
Figure 17 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/20/126-FP).
Figure 18 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/45/006-FP).
Figure 19 shows XRPD pattern comparison of two different lots of 5-MeO-DMT benzoate. Figure 20 shows a DSC thermograph of another lot of 5-MeO-DMT benzoate.
Figure 21 shows additional XRPD characterisation of multiple lots of 5-MeO-DMT benzoate.
Figure 22 shows DSC thermograph results for 5-MeO-DMT benzoate lots Cl, DI and El.
Figure 23 shows TGA thermograph results for 5-MeO-DMT benzoate lots Cl, DI and El at 10°C.min 1.
Figure 24 shows XRPD pattern comparison of 5-MeO-DMT benzoate Pl (Toluene), QI (Chlorobenzene), and R1 (Anisole) against the XRPD pattern of Pattern A.
Figure 25 shows DSC thermographs of 5-MeO-DMT lots Pl, QI and R1 at 10°C.min -1.
Figure 26 shows DSC thermograph expansions of 5-MeO-DMT lots Pl, QI and R1 at 10°C.min -1.
Figure 27 shows TGA thermographs of 5-MeO-DMT lots Pl, QI and R1 at 10°C.min 1.
Figure 28 shows XRPD pattern comparison of 5-MeO-DMT benzoate lots R1 and R2 (thermally cycled suspensions) compared with a reference Pattern A XRPD diffractogram.
Figure 29 shows DSC thermographs of 5-MeO-DMT benzoate lots P2, Q2 and R2 at 10°C.min -1.
Figure 30 shows DSC thermograph expansions of 5-MeO-DMT benzoate lots P2, Q2 and R2 at 10°C.min -1.
Figure 31 shows TGA thermographs of 5-MeO-DMT benzoate lots P2, Q2 and R2 at 10°C.min -1.
Figure 32 shows XRPD pattern overlay of samples isolated via anti-solvent mediated crystallisation 5-MeO-DMT benzoate.
Figure 33 shows XRPD pattern overlay of 5-MeO-DMT benzoate lot Fl and a reference Pattern A form/material.
Figure 34 shows XRPD pattern overlay of 5-MeO-DMT benzoate samples isolated from cooling and a Pattern A reference.
Figure 35 shows XRPD pattern overlay of 5-MeO-DMT benzoate samples isolated from cooling post-particle size reduction and Pattern A reference.
Figure 36 shows XRPD pattern comparison for all samples from the reverse addition anti-solvent driven crystallisation of 5-MeO-DMT benzoate except for Al and Bl.
Figure 37 shows XRPD pattern comparison for 5-MeO-DMT benzoate F3 with a known Pattern A reference.
Figure 38 shows XRPD pattern comparison of 5-MeO-DMT benzoate Al and Bl.
Figure 39 shows XRPD patterns for 5-MeO-DMT benzoate Al, QI and a reference Pattern A pattern.
Figure 40 shows XRPD patterns for 5-MeO-DMT benzoate Bl, QI and a reference Pattern A pattern.
Figure 41 shows a DSC thermograph of 5-MeO-DMT benzoate sample Al at 10°C.min 1 isolated from methanol and toluene.
Figure 42 shows a DSC thermograph of 5-MeO-DMT benzoate Bl at 10°C.min-l isolated from isopropanol and toluene.
Figure 43 shows a DSC thermograph expansion of 5-MeO-DMT benzoate. Bl at 10°C.min-l isolated from isopropanol and toluene.
Figure 44 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E; E Particle size reduced and Pattern A reference. Figure 45 shows XRPD of 5-MeO-DMT benzoate lot 21-01-051 B, obtained from quenching the melt.
Figure 46 shows XRPD of 5-MeO-DMT benzoate lot 21-01-051 C, obtained by lyophilisation.
Figure 47 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 B after 20 hours, C after 20 hours, and Pattern A reference.
Figure 48 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E; E particle size reduced, and Pattern A reference.
Figure 49 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 A, C, and D at lO’C.min-1, isolated from acetone concentrate, 051 A, and lyophilisation, 051 C and 051 D.
Figure 50 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 C and C post 20 hours at 10’C.min 1.
Figure 51 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-051 D, large scale lyophilised material, with temperature stamps corresponding to hot-stage microscopy images.
Figure 52 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 30.02°C.
Figure 53 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 54.21°C.
Figure 54 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 74.21°C.
Figure 55 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 114.23°C.
Figure 56 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 120.14°C.
Figure 57 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation.
Figure 58 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 M isolated from the equilibration of amorphous 5-MeO-DMT benzoate in a,a,a-trifluorotoluene with thermal modulation with lot 20-37-64 (Pattern A).
Figure 59 shows DSC thermograph comparison of a selection of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A.
Figure 60 shows DSC thermograph expansion comparison of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A, highlighting an event in lot 21-01-054 Q, solid isolated from anisole.
Figure 61 shows Expanded DSC thermograph expansion highlighting an event in lot 21-01-054 Q, isolated from anisole.
Figure 62 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 2 minutes, lot 21-01- 049 Bl, Pattern B, and lot 20-37-64, Pattern A.
Figure 63 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 1 hour and lot 21-01- 060 Al-air dried 2 minutes.
Figure 64 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 2 minutes, lot 21-01- 060 Al-air dried 1 hour, and lot 21-01-049 Bl, Pattern B.
Figure 65 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour.
Figure 66 shows DSC thermograph expansion of 5-MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour. Figure 67 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 20 hours, lot 21-01- 060 Al air dried 2 minutes, and lot 21-01-049 Bl, Pattern B reference.
Figure 68 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 2 mins and Al isolated immediately then air dried for 2 minutes.
Figure 69 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 20 hours and Bl isolated after 3 hours equilibration then air dried for 2 minutes, and lot 21-01-049 Bl, Pattern B.
Figure 70 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 solids isolated from amorphous 5-MeO-DMT benzoate exposed to solvent vapour.
Figure 71 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 K, isolated from amorphous 5- MeO-DMT benzoate exposed to solvent vapour, with lot 20-37-64, Pattern A.
Figure 72 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-058 B, lot 21-01-058 F, lot 21-01- 058 K, and lot 21-01-062 G.
Figure 73 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 20-37-64, Pattern A, lot 21- 01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
Figure 74 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
Figure 75 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
Figure 76 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-058 D, isolated from exposure of anisole vapour to amorphous form.
Figure 77 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes).
Figure 78 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes).
Figure 79 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 D at 10°C.min-l.
Figure 80 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D.
Figure 81 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D.
Figure 82 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 C at 10°C.min-l.
Figure 83 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 A, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
Figure 84 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F and 21-01-073 F rerun.
Figure 85 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
Figure 86 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
Figure 87 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 K, 21-01-049 Bl, Pattern B, and 20-37-64.
Figure 88 shows XRPD of 5-MeO-DMT benzoate lot 21-01-078. Figure 89 shows DVS isothermal plot of 5-MeO-DMT benzoate lot 21-01-078.
Figure 90 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-078 (post-DVS) and 20-37-64.
Figure 91 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl).
Figure 92 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1.
Figure 93 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1; spectra separated.
Figure 94 shows Forced Swim Test results, Time Immobile, for 5-MeO-DMT benzoate, vehicle and imipramine.
Figure 95 shows Forced Swim Test results, Latency to Immobility, for 5-MeO-DMT benzoate, vehicle and imipramine.
Figure 96 shows 5-MeO-DMT Group Mean Plasma Concentration (ng/mL) in Male Beagle Dogs - Group 2 (HCI salt) and Group 4 (benzoate salt) - Dose Level (0.4 mg/kg); wherein the Mean Plasma Concentration of Groups 2 and 4 are substantially the same with dose time.
Figure 97 shows an XRPD of Pattern H.
Figure 98 shows a DSC thermograph of Pattern H.
Figure 99 shows a DSC thermograph of Pattern H.
Figure 100 shows a DSC thermograph of Pattern H.
Figure 101 shows a FTIR spectra of Pattern H compared with Pattern A.
Figure 102 shows a FTIR spectra of Pattern H compared with Pattern A.
Figure 103 shows a FTIR spectra of Pattern H.
Figure 104 shows a FTIR spectra of Pattern A.
Figure 105 shows an XRPD diffractogram for 5-MeO-DMT hydrochloride lot 20/20/126-FP.
Figure 106 shows an XRPD diffractogram for 5-MeO-DMT hydrochloride lot 20/45/006-FP.
Figure 107 shows the XRPD diffractogram of Figures 105 and 106 overlaid on top of one another.
Figure 108 shows a DSC and TGA thermograph of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP at 10°C/Min heating rate.
Figure 109 shows DSC thermographs of 5-MeO-DMT hydrochloride, lot 20/20/126-FP at 5°C/Min (Black), 10°C/Min (Red), 20°C/Min (Blue) and 40°C/Min (Green) heating rates.
Figure 110 shows a DSC and TGA thermograph of 5-MeO-DMT Hydrochloride, lot 20/45/006-FP at 10°C/Min heating rate.
Figure 111 shows DSC thermographs of 5-MeO-DMT hydrochloride, lot 20/45/06-FP at 5°C/Min (Black), 10°C/Min (Red), 20°C/Min (Blue) and 40°C/Min (Green) heating rates.
Figure 112 shows the DVS isotherm of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP.
Figure 113 shows the DVS isotherm of 5-MeO-DMT Hydrochloride, lot 20/45/006-FP. Figure 114 shows an optical micrograph of lot 20/20/126-FP of 5-MeO-DMT Hydrochloride at xlO magnification (A) and polarised (B).
Figure 115 shows optical micrographs of lot 20/20/126-FP of 5-MeO-DMT Hydrochloride at x50 magnification (A) and (B).
Figure 116 shows an optical micrograph of lot 20/45/006-FP of 5-MeO-DMT Hydrochloride at xlO magnification (A) and polarised (B).
Figure 117 shows an optical micrograph of lot 20/45/006-FP of 5-MeO-DMT Hydrochloride at x50 magnification (A) and (B).
Figure 118 shows that one-way ANOVA shows a main effect of treatment P<0.0001 on TNF-a release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. **** Significant difference compared to vehicle.
Figure 119 shows that one-way ANOVA shows a main effect of treatment P=0.0049 on IL-lfJ release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. *** Significant difference compared to vehicle. + Significant difference compared to LPS 2 ng/ml. ++ Significant difference compared to LPS 2 ng/ml.
Figure 120 shows that one-way ANOVA shows a main effect of treatment P<0.0001on IL-6 release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. ** Significant difference compared to vehicle. + Significant difference compared to LPS 2 ng/ml. ++ Significant difference compared to LPS 2 ng/ml.
Figure 121 shows that one-way ANOVA shows no effect of treatment P=0.2131 on IL- 10 release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5.
Figure 122 shows a summary of the synthetic route to prepare MDMA from piperonal.
Figure 123 shows a summary of the synthetic route to prepare MDMA (and related analogues) from safrole.
Figure 124 shows a schematic outlining the preparation of HF-MAPs.
Figure 125 shows HF-MAPs prepared when viewed using a light microscope.
Figure 126 (A) shows a comparison of percentage swelling over 240 minutes with 20% w/w Gantrez8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCOa ('super swelling') and 20% w/w Gantrez8 S-97+ 7.5% w/w PEG 10,000 ('normal swelling'). (B) shows a comparison of percentage swelling over 24 hours with 20% w/w Gantrez8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCOa ('super swelling') and 20% w/w Gantrez8 S-97+ 7.5% w/w PEG 10,000 ('normal swelling').
Figure 127 shows light microscope images of 20% w/w Gantrez8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCCh ('super swelling') before (A) and after (B) swelling in PBS.
Figure 128 shows a Graphical representation of the number of Parafilm® M layers penetrated, and percentage holes created within each layer following a 32 N force applied for 30 s for three MAP design. Means ± S.D., n = 3.
Figure 129 shows needle heights before and after compression of a 32 N force for 30 secs for the two MAP designs. Means + S.D., n = 3.
Figure 130 shows a schematic representation of the Franz cells setup used for ex vivo permeation studies.
Figure 131 shows (A) drug permeation %. Means + SD, n=3, (B) shows drug permeation quantity (mg). Means + SD, n=3.
Figure 132 shows (A) recovery % of both benzoate and HCI salts from each compartment at 24 hr. Means + SD, n=3, (B) shows quantity (mg) recovered from both benzoate and HCI salts from each compartment at 24 hr. Means + SD, n=3.
Figure 133 shows one embodiment of a microneedle array (1). Detailed description of the invention
Figure 1 shows a one-step synthesis of 5-MeO-DMT from the reaction of 4-methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanal dimethyl acetal. Figure 2 shows a three step synthesis of 5-MeO-DMT. The first step involves the reaction of 5-methoxyindole with oxalyl chloride. The resultant product is aminated with dimethylamine and then is reduced with lithium aluminium hydride. Figure 3 shows the schematic route for the formation of a powder form of 5-MeO-DMT using a spray drying process. In an embodiment, it is a powder form of 5-MeO-DMT benzoate which is formed.
Examples
Example 1: Synthesis of 5-MeO-DMT (the free base) in one step (the free base)
A schematic representation of this reaction is shown in Figure 1.
Hydrazine (1.0 eq), diethyl acetal (1.2 eq), and aqueous sulfuric acid (0.1 eq) where heated together at 65-75°C for 18 hours. MTBE (10 vol) was added, followed by adjustment to about pHlO using 12% caustic (about l.leq.). The layers were separated and the aqueous fraction back extracted with MTBE (lOvol). The combined organic fractions were washed with water (lOvol) twice, then evaporated to dryness under vacuum. Yield 100%.
Example 2: Synthesis of 5-MeO-DMT (the free base) in three steps
A schematic representation of this reaction is shown in Figure 2.
Step 1 - Add methyl tert-butyl ether (MTBE) (15vol) into the reaction vessel and cool to -20 to -30°C, before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. Add a solution of 5-methoxyindole (1.0 eq) in THF (lvol) to the reaction vessel, maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.
Cool the reaction to between -20 to -30°C and add a solution of methanol (lvol) and MTBE (lvol), maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C over no less than 30 minutes and stir for at least 1 hour.
Filter and wash the solids with MTBE cooled to 0-5°C. Add the washed filtered solids and methanol (20vol) to a reaction vessel. Heat to 60-65°C and stir for no more than 30 minutes. Cool to 0-5°C over no less than 2 hours and stir for no less than 2 hours. Filter and wash the solids with MTBE cooled to 0-5°C. Dry the solids obtained at no more than 40°C for no less than 12 hours. Yield 95%.
Step 2 - Add the compound obtained in step 1 (1.0 eq) to a reaction vessel together with dimethylamine hydrochloride (3.0 eq) and methanol (2vol). Add 25% NaOMe in methanol (3.5 eq), to the reaction maintaining the temperature at no more than 30°C. Warm to and stir for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remains. Adjust the temperature to 0-5°C over no less than 2 hours, then add water (5vol) over no less than 1 hour with stirring at 0-5°C for no less than 1 hour.
Filter and wash the solids with water cooled to 0-5°C, and dry the solids obtained at no more than 40°C for no less than 12 hours. Yield 85%.
Step 3 - Add the compound obtained in step 2 (1.0 eq) to a reaction vessel. Add IM LiAl H4 in THF (1.5 eq) in THF (8vol) to the reaction maintaining no more than 40°C. Heat at reflux for no less than 4 hours ensuring that no more than 2% of the starting material from step 2 remains.
Adjust to 0-5°C and add water (0.25vol) in THF (0.75vol) over no less than 30 minutes, maintaining no more than 10°C. Then add 15% caustic (0.25vol) maintaining the temperature at no more than 10°C. Add water (0.65vol) maintaining the temperature at no more than 10°C. Add THF (0.25vol) as a vessel rinse and stir the contents at 0- 5°C for no less than 30 minutes. Add sodium sulfate (100wt%) and stir contents at 0-5°C for no less than 30 minutes.
Filter and wash the solids with toluene (2xl0vol) and keep liquors separate. Recharge THF liquors to a clean vessel and distil under vacuum to minimum stir. Charge toluene liquors and distil under vacuum to about 10vol. Then add water (5vol) and stir for no less than 15 minutes. Stop, settle and remove aqueous layer to waste. Charge with 4% HCI to a pH of between 1-2 (about 4vol) and stir for no less than 15 minutes. Stop, settle and remove organic layer to waste. Charge MTBE (15vol). Charge with 15% caustic to a pH between 11-13 (about 0.9vol). Stir for no less than 15 minutes. Stop, settle and remove aqueous layer to waste. Charge with water (5vol). Stir for no less than 15 minutes. Stop, settle and remove the aqueous layer to waste.
Example 3: Synthesis of 5-MeO-DMT hydrochloride salt
5-MeO-DMT (the free base) is dissolved in toluene (1.0 to 2.5vol). Isopropyl alcohol (IPA) was then added (2.5vol) followed by 1.25M HCI in IPA (1.0 eq) and the temperature adjusted to 0-5°C over 1 hour. If no precipitation/crystallization occurs, toluene (6.25vol) is added over 30 minutes. The mixture was then stirred at 0- 5°C for 2 hours. The resultant solid is filtered, washed with toluene (3.8vol). The solid was dried under vacuum at ambient temperature. Yield 58%.
Example 3a: Synthesis of 5-MeO-DMT HCI
Herein disclosed, there is provided a method for the synthesis of 5-MeO-DMT hydrochloride salt (also referred to herein as 5-MeO-DMT hydrochloride or the hydrochloride salt). Herein disclosed, there is provided a purified form of 5-MeO-DMT hydrochloride obtained from a source of 5-MeO-DMT hydrochloride. In an aspect there is provided a purified mass of 5-MeO-DMT hydrochloride obtained from a source of 5-MeO-DMT hydrochloride. The skilled person would understand that a mass of 5-MeO-DMT hydrochloride is a commercially useful amount, for example not just a few crumbs of 5-MeO-DMT hydrochloride, or a few crystals, or a single crystal of 5-MeO-DMT hydrochloride.
In an embodiment, the purified mass is greater than 0.5, 1, 2, 5, 10, 20, 50, 100, 250, 500 or 1000 grams. In an embodiment, the purified mass is a commercially useful amount of 5-MeO-DMT hydrochloride. In an embodiment, a useful amount of 5-MeO-DMT hydrochloride is sufficient to provide more than 20, 50, 100, 250, 500, 1,000, 5,000, 10,000, 25,000, 50,000 or 100,000 pharmaceutically effective treatment doses for human subjects in need thereof. In an embodiment, the purified mass is not a single crystal. In an embodiment, the purified mass is not a few crystals 5-MeO-DMT hydrochloride. In an embodiment, the purified mass is not a few crumbs of 5-MeO-DMT hydrochloride. In an embodiment, the purified mass is not sufficient to provide less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 treatment doses for human subjects in need thereof. In an embodiment, the source of 5-MeO-DMT hydrochloride contains impurities. In an embodiment, the source of 5-MeO-DMT hydrochloride is less pure than the purified mass of 5- MeO-DMT hydrochloride. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride contains less/fewer impurities than the source of 5-MeO-DMT hydrochloride. In an embodiment, the source of 5-MeO-DMT hydrochloride contains more impurities than the purified mass of 5-MeO-DMT hydrochloride.
In an embodiment, there is provided a purified mass of 5-MeO-DMT hydrochloride. In an embodiment, the purified mass contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of any impurity. In an embodiment, the phrase 'any impurity' can be understood to mean 'any one impurity'. In an embodiment, the term 'purified' is may be understood to be equivalent with the term 'pure'. In an embodiment, the purified mass is substantially free of the hydroxyl impurity shown below:
•' T
In an embodiment, the purified mass contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of the hydroxyl impurity. In an embodiment, the source of 5-MeO-DMT hydrochloride contains more hydroxyl impurity than the purified mass of 5-MeO-DMT hydrochloride. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride contains less hydroxyl impurity than the source of 5-MeO-DMT hydrochloride. In an embodiment, the purified mass has a chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by HPLC or RP-HPLC. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride is crystalline. In an embodiment, the purified mass is characterised by one or more of: peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A; endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and/or a peak of between 142 and 148°C; enthalpy in a DSC thermograph of between 113J/g and -123J/g; onset of decomposition in a TGA thermograph of between 120 and 165°C. In an embodiment, the purified mass is characterised as described elsewhere in this document, such as in the Examples. In an embodiment, there is provided of obtaining a purified mass of 5-MeO-DMT hydrochloride, wherein a source of 5-MeO-DMT hydrochloride is base-treated, optionally the source of 5-MeO-DMT hydrochloride is basetreated with an aqueous basic solution. In an embodiment, of obtaining a purified mass of 5-MeO-DMT hydrochloride, wherein 5-MeO-DMT hydrochloride is base-treated, optionally the source of 5-MeO-DMT hydrochloride is base-treated with an aqueous basic solution. In an embodiment, the basic solution comprises an alkoxide, optionally the basic solution comprises sodium hydroxide, further optionally the basic solution is 5% aqueous sodium hydroxide. In an embodiment, the source of 5-MeO-DMT hydrochloride is suspended in a suspending organic solvent prior to being base-treated, wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the resultant base-treated reaction is partitioned with an extracting organic solvent to give an extract comprising the base-conditioned hydrochloride salt; wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the extract is reduced under vacuum to give a concentrate of the purified mass of 5-MeO-DMT hydrochloride, optionally the extract is concentrated to approximately 8 volumes, or further optionally the solvent is removed to give the purified mass of 5-MeO-DMT hydrochloride in a solid form. In an embodiment, the extract or solid form of the purified mass of 5-MeO-DMT hydrochloride is azeotropically dried with one or more batches of fresh extracting organic solvent wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride is obtained by filtration. In an embodiment, the filtered purified mass of 5-MeO-DMT hydrochloride is washed with a washing organic solvent. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride is washed with cooled washing organic solvent, optionally the washing organic solvent is cooled to below room temperature, is cooled to below 10°C, is cooled to below 5°C, or cooled to between 5 and 0°C. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride is dried under vacuum. In an embodiment, the suspending organic solvent, the washing organic solvent, and/or the extracting organic solvent is IPAc. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride is isolated and subjected to a recrystallisation process. In an embodiment, the method comprises the steps of: combining the source of 5-MeO-DMT hydrochloride and an organic solvent; optionally the organic solvent is IPAc adding a basic solution to the combined 5-MeO-DMT hydrochloride salt and organic solvent; optionally the basic solution is aqueous 5% NaOH; partitioning; washing the resulting organic phase with water; drying the solvent; optionally azeotropically with IPAc; and concentrating under vacuum.
In an embodiment, the method further comprises the steps of concentrating under vacuum to dryness. In an embodiment, the method further comprises the steps of: adjusting the solvent temperature to between about 50-55°C; adding one or more counter solvents in which the 5-MeO-DMT hydrochloride is substantially insoluble in; and/or adjusting the temperature to between about 0-5°C; filtering and washing with cold solvent; optionally the cold solvent is IPAc; and drying under vacuum to obtain the purified mass of 5-MeO-DMT hydrochloride in a solid form, optionally as a crystalline solid.
In an embodiment, the purified mass of 5-MeO-DMT hydrochloride produced is characterised by one or more of: peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A; endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and/or a peak of between 142 and 148°C; enthalpy in a DSC thermograph of between 113J/g and -123J/g; onset of decomposition in a TGA thermograph of between 120 and 165°C.
In an embodiment, there is provided a purified mass of 5-MeO-DMT hydrochloride obtained by the method described previously or subsequently. In an embodiment, there is provided an inorganic or organic acid salt of 5- MeO-DMT obtained by the step of treating the purified mass of 5-MeO-DMT hydrochloride as defined previously or subsequently, or obtained by the method previously or subsequently, with an inorganic acid or organic acid; wherein the resultant counter anion is the deprotonated form of the acid used, wherein optionally the resultant counter anion is a fluoride, bromide, iodide, fumarate, acetate, succinate, oxalate, acetate, citrate, triflate or benzoate anion; further optionally the anion is the benzoate. In an embodiment, there is provided >100g of purified 5-MeO-DMT hydrochloride. In an embodiment, there is provided >200g of purified 5-MeO-DMT hydrochloride. In an embodiment, there is provided >300g of purified 5-MeO-DMT hydrochloride. In an embodiment, there is provided >400g of purified 5-MeO-DMT hydrochloride. In an embodiment, there is provided >500g of purified 5-MeO-DMT hydrochloride. In an embodiment, there is provided a method of synthesizing >100g, >200g, >300g, >400g or >500g of purified 5-MeO-DMT hydrochloride. Herein disclosed, there is provided 5-MeO-DMT hydrochloride which contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of any impurity. In an embodiment, the 5-MeO-DMT hydrochloride is substantially free of the hydroxyl impurity shown below:
In an embodiment, the 5-MeO-DMT hydrochloride contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT hydrochloride has a chemical purity of greater than 95, 96, 97, 98, 99 or 99.5%. In an embodiment, the 5-MeO-DMT hydrochloride has a chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by HPLC or RP-HPLC. In an embodiment, the 5-MeO-DMT hydrochloride is crystalline. In an embodiment, the crystalline 5-MeO-DMT hydrochloride is characterised as described elsewhere in this document, such as in the Examples. In an embodiment, there is provided pure 5-MeO-DMT hydrochloride. In an embodiment, this may be crystalline. In an embodiment, the source of 5-MeO-DMT hydrochloride is isolated as a solid or a solution or dispersed in a carrier medium e.g. a solvent. In an embodiment, the source of 5-MeO-DMT hydrochloride is obtained from the reaction of the free base of 5-MeO-DMT with hydrochloride. In an embodiment, the source of 5- MeO-DMT hydrochloride is obtained from the reaction of the free base of 5-MeO-DMT with hydrochloride wherein the reaction takes place in a solvent wherein the solvent may be one or more of toluene, IPA or IPAc. In an embodiment, the source of 5-MeO-DMT hydrochloride is obtained as described in the Examples.
Example 4: Synthesis of 5-MeO-DMT benzoate salt
5-MeO-DMT (the free base) is dissolved in toluene (1 eq) and benzoic acid (1 eq) in toluene (lOvol) is added over a period of 20 minutes and stirred at room temperature for 2 hours. The resultant precipitation/crystallization was filtered and washed with toluene (2.5vol) and dried under vacuum at room temperature. Isopropyl acetate (IPAc) (15.8vol) was added to the solids obtained above and the temperature was raised to about 73°C until the solid dissolved. The solution was allowed to cool to 0-5°C over 2 hours and this temperature was maintained for 1 hour with stirring. The resultant benzoate salt was filtered and vacuum dried at room temperature. Yield 68%.
Advantageously, the benzoate salt of 5-MeO-DMT has improved characteristics over the common hydrochloride salt, including reduced mucosal irritation, increased epithelial permeability and increased stability.
5-MeO-DMT benzoate is a white to off white solid powder, soluble in water at >50mg/ml with a pH of 7-8 at 50mg/ml and a pKa of 9.71.
Example 4a: An improved method of 5-MeO-DMT benzoate synthesis
A method for synthesising 5-MeO-DMT benzoate comprises the reduction of compound (1), this reaction requires refluxing in a large excess of lithium aluminium hydride and proceeds via a partially-reduced hydroxy impurity (2), see the reaction scheme below:
The initial reduction proceeds quite quickly. However, to reduce the hydroxy impurity all the way to (3) is more difficult to achieve and requires extended stir-out times at reflux. Even under such conditions it has proven difficult to reduce the hydroxy impurity level down to less than 1.5%. Under such aggressive conditions there runs the risk of degrading (3) in trying to achieve reaction completion either by charging additional lithium aluminium hydride or extending the time at reflux.
Surprisingly, the inventors have discovered that isolating (3) as the HCI salt followed by a salt break process and benzoate salt formation greatly improves the purging (2). Under the more acidic conditions of the HCI salt formation, dehydration of the impurity can occur to give two more readily purged species (4) and (5), see the reaction scheme below:
The above disclosed improved method allows for the provision of batches of 5-MeO-DMT benzoate in which the levels of the hydroxyl impurity are very low, 0.1% or lower, compared with 1.5% for the aforementioned method.
In an embodiment, it is the hydrobromide salt which is produced by the above method, wherein HBr is added in place of benzoic acid. In an embodiment, it is any other herein described salt which is produced by the above method, wherein the benzoic acid is replaced by the corresponding acid, e.g. oxalate, oxalic acid.
Example 4b: Generation of benzoate salt from hydrochloride salt
The 5-MeO-DMT hydrochloride salt was taken up in 6 volumes of IPAc and then 1 equivalent of aqueous sodium hydroxide solution added. Following a pH check to confirm the solution was basic, layers were separated and the solution of 5-MeO-DMT free base in IPAc washed with water. After azeotropic distillation under reduced pressure to dry the batch the benzoate salt was formed by the addition of a solution of benzoic acid in IPAc at elevated temperature. Product was isolated by filtration following a cool-down and stir-out phase. As the salt formation is included as part of the process it was found that an increase in the overall volume of IPAc compared to that used for a standalone benzoate salt recrystallisation was beneficial. This allowed for the addition of the benzoic acid solution to be carried out within an acceptable temperature range (50-55 °C) whilst retaining everything in solution. The benzoate salt procedure was successfully demonstrated on a 10 g scale and a 150 g scale. A significant improvement in final product purity was achieved, with the hydroxy impurity much reduced, when compared with formation of the benzoate salt straight from the free base. The purity was assayed by HPLC (%area) and 0.12 (%area) of the intermediate hydroxy impurity was found. The procedure used to generate 5-MeO-DMT benzoate from the hydrochloride salt is detailed below:
Charge 5-MeO-DMT HCI to vessel, Charge IPAc (6 vol) to vessel and start stirrer, Adjust batch temperature to 15- 25°C, Charge 5% sodium hydroxide solution (1.0 eq) to vessel, maintaining temperature at NMT 30°C, Stir contents of CL3667 at 15-25°C for NLT 30 mins, Turn of agitator and allow phases to settle, Separate lower aqueous layer as waste, Charge water (5 vol) to vessel, Stir contents of CL3667 at 15-25°C for N LT 30 mins, Turn off agitator and allow phases to settle, Separate lower aqueous layer as waste, Charge IPAc (3 vol) to vessel, Distil to approx. 8 vols under vacuum at NMT 50°C, Charge IPAc (3 vol) to vessel, Distil to approx. 7.5 vols under vacuum at NMT 50°C, An in-line filtration can be carried out at this point in the procedure (followed by line rinse), Charge a solution of benzoic acid (1.0 eq) in IPAc (8.5 vol) to the batch, maintaining a temperature of 50-55 °C during the addition, Adjust batch temperature to 40-45 °C and stir for N LT 30 minutes, Confirm batch has crystallized, If it has not crystallized, continue stirring for up to 2 hours, If batch has still not crystallized, seek technical advice, Adjust batch temperature to 0-5 °C over NLT 2 hours, Stir batch at 0-5 °C for NLT 2 hours, Isolate by filtration, Wash the filter cake with IPAc (2.3 vol) at 0-5 °C, Dry at NMT 40 °C for NLT 12 hours.
Example 4c: Conversion of benzoate salt to hydrochloride salt
A procedure was developed to convert 5-MeO-DMT benzoate salt to the hydrochloride salt. 5-MeODMT benzoate salt was taken up in 15 volumes of toluene and then 1 equivalent of aqueous sodium hydroxide solution added. Following a pH check to confirm the solution was basic, layers were separated and the solution of 5-MeODMT free base in toluene washed with water. After azeotropic distillation under reduced pressure the hydrochloride salt was formed by the addition of a solution of hydrogen chloride in IPA at elevated temperature. Product was isolated by filtration following a cool-down and stir-out phase. The hydrochloride salt was generated in 78% yield, It is of note that the intermediate hydroxy impurity present in the benzoate input material purged particularly well when isolating the hydrochloride salt, being present at a level of 0.1% compared to 0.7% present in the 5-MeODMT benzoate input material.
Example 5: Synthesis of 5-MeO-DMT fumarate salt
5-MeO-DMT (the free base) is added to a solution of fumaric acid (0.5 eq) in IPA over 15 minutes at 40-45°C. The resultant solution was cooled at room temperature and stirred for 16 hours. The solution was then cooled to 0-5°C with stirring for 2 hours. The resulting precipitation/crystallization was filtered and was rinsed with toluene (2.5vol). Yield 68%.
Example 5a: Conversion of hydrochloride salt to fumarate salt
5% sodium hydroxide solution (23.3 g) was added portion wise to a suspension of 5-MeO-DMT HCI (10 g) in toluene (15 vols). The resulting biphasic solution was stirred for 30 min followed by phase separation. The organic phase was washed with water (10 vols) followed by phase separation and concentrated to 2 vols under vacuum at NMT 55°C. IPA (3 vols) was charged and the batch solution was distilled to 2 vols. This solvent exchange/distillation process was repeated a further two times. A solution of fumaric acid (2.3 g, 0.5 eq) in toluene (9.2 vols) was added to the IPA solution at 40-45°C. The resulting slurry was cooled to 0-10°C, filtered and the cake washed with IPA (2.5 vols). The wet cake was dried under vacuum at ambient temperature. 5-MeO-DMT fumarate was isolated in 76% yield. The Table below summarises the purity of the isolated fumarate and the input 5-MeO-DMT HCI salt.
5-MeO-DMT fumarate was successfully prepared from the HCI salt in good yield and good purity. Use of the hydrochloride salt in this process has allowed the fumarate salt to be isolated with a low level of hydroxy impurity. Production of 5-MeO-DMT fumarate by the method detailed in Example 5 resulted in a 70% yield with 93.91% purity and 5.07% of the hydroxy impurity present. In an embodiment, there is provided a method for the synthesis of 5- MeO-DMT fumarate from 5-MeO-DMT HCI.
A schematic route for the preparation of a powder form of 5-MeO-DMT (or the salt thereof) is shown in Figure 3. The three main steps in the process are:
1. Spray drying a solution containing the substance(s) of interest (e.g. 5-MeO-DMT, or the salt, thereof inclusive of any excipients). This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
2. Drying of the atomized droplets (e.g. with nitrogen gas, optionally at an elevated temperature). 3. Separating and collecting the dried particles from the gas stream (e.g. using a cyclone separator to capture the required size fraction).
In an embodiment, a ProCepT spray dryer is used. In an embodiment, a ProCepT spray dryer with an ultrasonic nozzle is used. In an embodiment, there is dissolution of 5-MeO-DMT benzoate and HPMC in water to make input solution at a 50:50 ratio.
Example 7: Slug Mucosal Irritation assay
The Slug Mucosal Irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potency of pharmaceutical formulations and ingredients. The test utilizes the terrestrial slug Arion lusitanicus. The body wall of the slugs is a mucosal surface composed of different layers. The outer single-layered columnar epithelium that contains cells with cilia, cells with micro-villi and mucus secreting cells covers the subepithelial connective tissue. Slugs that are placed on an irritating substance will produce mucus. Additionally tissue damage can be induced which results in the release of proteins and enzymes from the mucosal surface. Several studies have shown that the SMI assay is a useful tool for evaluating the local tolerance of pharmaceutical formulations and ingredients. A classification prediction model that distinguishes between irritation (mucus production) and tissue damage (release of proteins and enzymes) has been developed. Furthermore, several studies with ophthalmic preparations have shown that an increased mucus production is related to increased incidence of stinging, itching and burning sensations. In 2010 a clinical trial was set up to evaluate the stinging and burning sensations of several diluted shampoos. A 5% shampoo dilution or artificial tears were instilled in the eye and the discomfort was scored by the participants on a 5 point scale during several time points up to 30 min after instillation. The same shampoos were tested in the SMI assay using the Stinging, Itching and Burning (SIB) protocol. This study showed that an increased mucus production was related with an increased incidence of stinging and burning sensations in the human eye irritation test. The relevance of the assay to reliably predict nasal irritation and stinging and burning sensations was demonstrated using several OTC nasal formulations, isotonic, and hypertonic saline.
Furthermore, the test was validated using reference chemicals for eye irritation (ECETOC eye reference data bank). These studies have shown that the SMI assay can be used as an alternative to the in vivo eye irritation tests. Moreover, a multi-center prevalidation study with four participating laboratories showed that the SMI assay is a relevant, easily transferable and reproducible alternative to predict the eye irritation potency of chemicals. The purpose of this assay was to assess the stinging, itching or burning potential of the test item(s) defined below. Using the objective values obtained for the mucus production the stinging, itching or burning potential of the test item(s) can be estimated by means of the prediction model that is composed of four categories (no, mild, moderate and severe).
Control items:
• Negative control - Name : Phosphate buffered saline (PBS)
• Positive control - Name : 1% (w/v) Benzalkonium chloride in PBS
Test items:
Compound 1
Name: 10% (w/v) Disodium fumarate in PBS
CASRN: 17013-01-3
Batch: KBSJ-PO
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Compound 2
Name: 10% (w/v) Sodium phosphate monobasic in PBS
CASRN: 7558-80-7
Batch: 2A/220991
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Compound 3
Name: 10% (w/v) Sodium acetate in PBS CASRN: 127-09-3
Batch: 5A/233258
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Name: 10% (w/v) Sodium citrate in PBS
CASRN: 68-04-2
Batch of vial: 5A/241516
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Test System: Slugs (Arion lusitanicus); 3 slugs per treatment group. The parental slugs of Arion lusitanicus collected in local gardens along Gent and Aalter (Belgium) are bred in the laboratory in an acclimatized room (18-20°C). The slugs are housed in plastic containers and fed with lettuce, cucumber, carrots and commercial dog food.
Test Design: A single study was performed. Treatment time was 15 minutes three times on the same day.
Slugs weighing between 3 and 6 g were isolated from the cultures two days before the start of an experiment. The body wall was inspected carefully for evidence of macroscopic injuries. Only slugs with clear tubercles and with a foot surface that shows no evidence of injuries were used for testing purposes. The slugs were placed in a plastic box lined with paper towel moistened with PBS and were kept at 18 - 20°C. Daily the body wall of the slugs was wetted with 300 pl PBS using a micropipette.
Test Procedure:
The stinging, itching or burning potency of the test item(s), was evaluated by placing 3 slugs per treatment group 3 times a day on 100 pL of test item in a Petri dish for 15 ± 1 min. After each 15-min contact period the slugs were transferred for 60 min into a fresh Petri dish on paper towel moistened with ImL PBS to prevent desiccation. An overview of this can be seen in Figure 4.
Mucus Production:
The amount of mucus produced during each contact period was measured by weighing the Petri dishes with the test item before and after each 15-min contact period. The mucus production was expressed as % of the body weight. The slugs were weighed before and after each 15-min contact.
Classification prediction model
Based on the endpoint of the SMI assay the stinging, itching or burning potency of the test item(s) was estimated using a classification prediction model.
The evaluation of the test results was based upon the total amount of mucus production during 3 repeated contact periods with the test item.
For each slug, the mucus production was expressed in % of the body weight by dividing the weight of the mucus produced during each contact period by the body weight of the slug before the start of that contact period. The total mucus was calculated for each slug and then the mean per treatment group was calculated. The classification prediction model shown in Table 1 was used to classify the compounds.
Table 1 Cut-off values for classification - potency for nasal mucosal discomfort > 17.5% Severe nee criteria
Before a test was considered valid, the following criteria must be met: the negative control should be classified as causing no stinging, itching and burning (Total mucus production < 5.5%) the positive control item should be classified as causing severe stinging, itching and burning (Total mucus production > 17.5%)
Irritation Potential
Table 2 Amount of mucus produced (MP) during each 15-min contact period (CP) and total amount of mucus produced
NC: negative control; PC: positive control; BAC: benzalkonium chloride
1Mean ± SD, n=3
2 No: total MP < 5.5%; Mild: 5.5% < total MP < 10%; Moderate: 10% < total MP < 17.5%; Severe: total
MP > 17.5%
The average amount of mucus produced during each 15-min contact period and total mucus production (total MP) is presented in Table 2. According to the classification prediction model of the SMI test, the negative control (untreated slugs) did not induce reactions in the slugs (mean total MP < 5.5%). The positive control on the other hand (DDWM/SLS 80/20) induced a high mucus production during each contact period (mean total MP > 17.5%) resulting in a classification as severe stinging, itching, and burning (SIB) reactions. The acceptance criteria were met and the experiment was considered valid.
In total, 4 different solutions were tested. The amount of mucus produced during each 15-min contact period was between 10% and 17.5%, indicating moderate SIB reactions. The test items can be ranked according to increasing total mucus production: sodium acetate (10% w/v) < sodium citrate (10% w/v) < disodium fumarate (10% w/v) < sodium phosphate (10% w/v).
Numerical Data
Table 3 Amount of mucus produced (MP) during each 15-min contact period (CP) and total amount of mucus produced
NC: negative control; PC: positive control; BAC: benzalkonium chloride 1Mean ± SD, n=3
2 No: total MP < 5.5%; Mild: 5.5% < total MP < 10%; Moderate: 10% < total MP < 17.5%; Severe: total MP > 17.5%
Table 4 Amount of mucus produced (MP) during each 30-min contact period (CP) and total amount of mucus produced (Code 00E04)
Table 5 Amount of mucus produced (MP) during each 60-min contact period (CP) and total amount of mucus produced
Table 6 Amount of mucus produced (MP) during a 60-min contact period (CP) Results
The total MP for a 60-min treatment (historical data) was compared with the total MP of the SIB protocol (3x 15- min treatment; current data). In the table below a ranking is proposed from least SIB reactions to highest SIB reactions:
Sodium oxalate appears to be the most irritating salt since a 1% concentration results in 11.2% total MP after 1 hour of contact. Sodium benzoate is the least irritating salt.
Example 8: Further slug mucosal irritation (SMI) testing
5-MeO-DMT as a freebase compound is known to be highly irritating to the mucosal lining; therefore, it is commonly prepared as a salt for insufflation. The hydrochloride (HCI) salt of 5-MeO-DMT is most commonly used due to ease of crystallisation. However, it is known that the HCI salt of 5-MeO-DMT is still quite irritating to the mucosal lining.
Following the results above indicating that sodium benzoate is the least irritating salt of those studied; further SMI testing was performed on 5-MeO-DMT benzoate and the common 5-MeO-DMT HCI salt according to the previously described methods (of Example 7). The results of this are shown below:
The 5-MeO-DMT benzoate produced 'mild' irritation compared to the 5-MeO-DMT HCI which scored as 'moderate' on testing.
Example 9: Permeation data
The use of ovine nasal epithelium to study nasal drug absorption is a technique which is well known to the person skilled in the art.
The permeation of 5-MeO-DMT benzoate and 5-MeO-DMT HCI has been studied by the current applicants. Dosing solutions corresponding to 1.25% concentration were prepared in water and applied to ovine nasal epithelium. The average cumulative (pg/cm2) of permeation of the benzoate and hydrochloride salt are shown in the table below (mean ± SD, n=5): The cumulative amount of 5-MeO-DMT benzoate and 5-MeO-DMT hydrochloride which permeated through ovine nasal epithelium per unit area following application of 1.25% dosing solutions prepared in water (mean ± SD, n=5) can be seen in Figure 5.
As can clearly be seen, the benzoate salt has higher permeation across the epithelium.
The above data obtained in the above test show that the 5-MeO-DMT benzoate salt gives higher permeation with less mucosal irritation than the commonly used HCI salt; and so this combination of properties makes the benzoate salt an ideal candidate for mucosal delivery. For example, less 5-MeO-DMT benzoate salt may be needed by inhalation to provide the same benefit as the HCI salt and the benzoate salt is less irritating, and so provides a synergistic benefit. Smaller amounts of compound also make inhalation easier to accomplish.
Example 10: Effects on the Central Nervous System Function
In the following examples, BPL-5MEO refers to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).
In the following examples, the hydrochloride salt of 5-MeO-DMT was used.
The following Examples (10-14) summarizes applicant-sponsored safety pharmacology studies to assess the effects of BPL-5MEO on CNS, cardiovascular system, and respiratory system function. The study designs are based on in the International Council for Harmonisation (ICH) S7A/B Guidance and were conducted in compliance with GLP regulations.
The pharmacological effects of BPL-5MEO on CNS function was assessed using a Functional Observational Battery (FOB) in male Sprague-Dawley rats following a single intranasal administration (ITR study 15951).
The test and control/vehicle items were administered by single dose intranasal administration to both nostrils, as shown in Table 7.
Table 7: Experimental Design of Study 15951 a The observers performing the FOB were not aware of the specific treatment administered to the animals. b Control animals were administered 0.1% hydroxypropyl methyl cellulose (HPMC) in water, c Dose volume did not exceed 25 pL/nostril for all animals regardless of their bodyweight.
Parameters monitored included mortality and clinical signs. General behavioral changes were assessed using FOB at 6 time points: before dosing, and at 15 minutes, 1, 2, 4, and 24 hours postdosing. On each occasion, the FOB was performed at 4 stages: when the animals were in their home cage, while handling the animals, when the animals were freely moving in an open-field, and when they received diverse stimuli for reactivity evaluation. The body temperature and neuromuscular strength were also measured on each of the occasions detailed above.
The FOB examinations were grouped according to functional domains of the nervous system as shown in Table 8.
Table 8: Functional Domains of the Nervous System and Associated Observations
There was no treatment-related mortality/morbidity. Transient BPL-5MEO-related clinical signs were noted immediately following dosing and consisted mainly of decreased activity, lying on the cage floor, shallow/increased respiration and dilated pupils at all dose groups. Tremors, salivation, and gasping were observed in some animals at the 3 and lOmg/kg doses, and twitching was noted in one animal at lOmg/kg. In the behavioral domain of the FOB, a single intranasal administration of BPL-5MEO at doses of 1.5, 3, and lOmg/kg resulted in transient decreased activity, lying on the cage floor, and decreased rearing at 15 minutes postdose. All behavioral parameters were comparable to control animals at 1-hour postdose. In the neurological (sensorimotor) /neuromuscular domain of the FOB, a single intranasal administration of BPL-5MEO at 1, 5, and lOmg/kg resulted in transient changes in gait (difficulty in movement) at all dose levels. All neurological (sensorimotor) /neuromuscular parameters were comparable to control animals at 1-hour postdose. In the autonomic domain, a single intranasal administration of BPL-5MEO of 1, 5, and lOmg/kg was associated with salivation, piloerection, increased respiration, dilated pupils and changes in body temperature was noted across all dose levels. All autonomic parameters were comparable with control animals at 2 hours postdose. In conclusion, the single intranasal administration of BPL-5MEO at doses of 1.5, 3, and lOmg/kg resulted in transient clinical signs, consistent with observable changes in behavior, neurological (sensorimotor) /neuromuscular and autonomic parameters which were fully resolved within 1 or 2 hours following dosing.
Example 11: Effects on Cardiovascular Function
In Vitro Study
The in vitro effect of 5-MeO-DMT on the hERG potassium channel current (iKr), the rapidly activating, delayed rectifier cardiac potassium current, was assessed using the patch clamp technique in stably transfected human embryonic kidney (HEK-293) cells that expressed the hERG gene (CRL study 1020-5458). This assay is employed as a screen to assess potential risks for Q.T interval prolongation.
The study was conducted in 2 phases: Phase 1 assessed the onset and steady-state inhibition of hERG at a selected concentration of 30pm 5-MeO-DMT; Phase 2 assessed the concentration response if the results from Phase 1 showed inhibition of 20% or more. The initial concentration of 30pm was selected based on the results of an exploratory dose-range finding study in dogs, where intranasal administration of 2.5mg/kg BPL-5MEO resulted in a mean Cmax of 803 ng/mL (3.67 pM) 5-MeO-DMT. A solution of 30 pM used in Phase 1 provided an 8-fold margin over this concentration.
In Phase 1, the 30 pM concentration of 5-MeO-DMT in protein free perfusate inhibited hERG potassium ion current by 77.8 ± 7.4% (n=3). Therefore, Phase 2 was undertaken using concentrations of 1, 3, 10, and 35pm 5-MeO-DMT in protein free perfusate (corresponding to 0.2, 0.6, 2.0, and 7.2 pg/mL of unbound drug substance). In Phase 2, 5- MeO-DMT inhibited hERG potassium ion channel current in a concentration-dependent manner as presented in Table 9. Table 9: Mean Percent Inhibition of hERG Potassium ion Channel Current by 5-MeO-DMT (in protein free perfusate)
The calculated IC50 of 5-MeO-DMT for hERG potassium channel current was 8.69pm (95% confidence limits 5.78- 13.06pm) compared to 12.8 nM (95% confidence limits 6.8-24.3 nM) for the positive control, terfenadine.
In Vivo Study
The pharmacological effects of BPL-5MEO on cardiovascular function (arterial blood pressure and ECG) was monitored by telemetry, in conscious male beagle dogs, following a single intranasal administration.
The highest dose level was selected based on the results from an intranasal maximum tolerated dose (MTD) toxicity study in dogs (Study 62958) where repeated daily dosing 2.5mg/kg/day of BPL-MEO once daily for 5 consecutive days was marginally tolerable and associated with transient clinical observations of moderate to severe incoordination, vocalization, salivation, shaking, circling, sneezing, decreased activity, and labored respiration that resolved within 60 minutes post dosing. Therefore, the highest dose selected for this study was 1.2mg/kg/day. The lowest dose of 0.4mg/kg/day was based on consideration of a maximum clinical dose of 14mg/day, with the middose of 0.8mg/kg/day selected to provide a dose-response assessment.
BPL-5MEO and control/vehicle were administered by intranasal instillation to both nostrils per session to a total of 4 dogs. Each dog received 4 administrations (control/vehicle and 3 dose levels of BPL-5MEO) according to a Latin- square design, such that each dog received the various administrations in a unique sequence, as in Table 10. A washout period of at least 2 days was allowed between each successive dose.
Table 10: Latin-square design for Dog Cardiovascular Study a Animal 1004A was replaced prior to dosing for Test Session 3 with animal 1104A due to low implant battery.
Low Dose, Mid Dose, High Dose were 0.4, 0.8, and 1.2mg/kg/day, respectively. The nominal dose levels refer to the freebase of 5-MeO-DMT salt form. The dose volume administered to each animal was 7 pL/kg/nostril. No animal exceeded a dose volume of 100 pL/nostril. The Control/Vehicle was 0.1% hydroxypropyl methyl cellulose (HPMC) in water.
The telemetry signals for arterial blood pressure and pulse rate, ECGs (heart rate [HR], RR, PR, Q.T, and QTcV intervals and QRS complex duration), body temperature, and locomotor activity, were recorded continuously over the telemetry recording period of at least 1.5 hours before the start of dosing and for at least 24 hours postdosing. Systolic, diastolic and mean arterial blood pressures and pulse rate were obtained from transmitter catheter inserted into the femoral artery. ECGs were obtained from the biopotential leads, from the telemetry transmitter, in a Lead II configuration.
During the study, all animals were also monitored for mortality and clinical signs. Body weights were recorded for general health status check and for dose calculation purposes only. There were no deaths and no BPL-5MEO-related clinical signs during the study. The morphology of the P-QRS-T waveforms remained normal and no rhythm or conduction abnormalities were observed in the ECGs between control and treated groups. There were minor differences in the % change of mean HR averaged between approximately 0 and 150 minutes postdose between all dose levels and the control vehicle. While mean % increases in mean HR increased by 3.7% in the control vehicle during this period, compared to baseline, the observed increases with the low, mid and high dose levels of BPL- 5ME0 were respectively 7.6%, 10.3%, and 17.2%. However, arterial blood pressure did not seem to show any appreciable differences that were sufficient to have any effect on HR. No other findings were observed. The observed increases in mean HR with all dose levels were non-adverse, reversible and did not show a typical dose relationship.
In conclusion, the single intranasal instillation of BPL-5MEO to both nostrils at doses of 0.4, 0.8, and 1.2mg/kg/day was well tolerated and did not result in any effects on the cardiovascular system of conscious male Beagle dogs.
Example 12: Absorption and Pharmacokinetics
In a 14-day intranasal toxicology in male and female rats (ITR report 700041), plasma concentrations of 5-MeO-DMT increased as a function of the dose administered. Peak (Cmax) concentrations were reached within 2 to 5 minutes post dosing (Tmax) with apparent ti/2 ranging from 6.8 to 9.4 minutes. Values trended lower on Day 14 compared to Day 1. There was no apparent sex difference and no evidence of accumulation with repeated dosing. In a 14-day intranasal toxicology study in male and female dogs (ITR report 62959), plasma concentration of 5-MeO-DMT increased as a function of the dose administered. Peak concentrations were reached within 3 to 14 minutes (Tmax), post dosing with apparent elimination half-lives ranging from 19 to 95 minutes. The values were not markedly different on Day l and Day 14. There was no apparent sex difference and no evidence of accumulation with repeated dosing.
The data shows that across the dose ranges studied in rats (5, 20, 75mg/kg), and dogs (0.4, 0.8, 1.5, and 2.5mg/kg), exposure was generally increased dose-dependently, but not consistently in a dose-proportional manner as some increases were more or less than dose-proportional between different doses. The results do not indicate a saturation of MAOA-mediated metabolism at the doses studied in these species as seen previously in mice.
Example 13: Toxicology
The toxicology program completed with BPL-5MEO consisted of non-pivotal single/repeat dose intranasal studies to determine the MTD in order to help select the highest doses for the pivotal 14-day GLP intranasal toxicology studies in male and female Sprague Dawley rats and Beagle dogs. The intranasal route of administration was used as this is the clinical route of administration. The species selected were based upon information from the published literature, preliminary PK information, availability of historical control information from the testing laboratory, and their standard use and acceptance as appropriate surrogates for intranasal administration. The experimental design of the pivotal 14-day studies included an assessment of systemic exposures (toxicokinetics) and a 14-day recovery period to assess reversibility of any adverse or delayed responses. The once daily dosing for 14 consecutive days in the pivotal studies was intended to provide sufficient systemic exposure to characterize the toxicity potential for a drug substance with a very short half-life.
1. Non-pivotal Single/Repeat Dose and Tolerance Studies a. Maximum Tolerated Dose Followed by 7-Day Repeat-Dose Toxicology in Rats (Study 700040)
The objectives of this non-GLP study were to determine the maximum tolerated dose and the toxicity profile of BPL- 5MEO following intranasal instillation in the rat. The study consisted of 2 parts. The objective of the first part (Dose Escalation Phase), was to determine the MTD of BPL-5MEO following a single intranasal administration to Sprague- Dawley rats. The doses used in part 1 were 15, 30, 50, 65, and 75mg/kg. Each subsequent dose was administered following at least 24 hours from the commencement of the previous dose. There were 2 males and 2 females in each dose group. The objective of the second part (Main Study Phase), was to determine the toxicity of BPL-5MEO at the MTD of 75mg/kg following once daily intranasal administration for 7 consecutive days to Sprague-Dawley rats.
All the dose formulation samples collected and analyzed were between 89.2% and 101.3% of nominal concentration, and as such met the acceptance criteria for accuracy (100 ±15% of their nominal concentration). Analysis was performed using a non-GLP HPLC-UV assay.
All female groups received their targeted doses in both parts. However, as the maximum feasible loading dose was not to exceed 25 pL/naris, regardless of body weight, mean achieved doses for the males at the 30 were still 99.3%, 90.0%, 88.2%, and 89.6%, respectively and were considered to be acceptable.
During Phase I, assessments of mortality, clinical signs and body weights were performed. All animals were observed for 14 days after dosing, following which they were euthanized on Day 15 and subjected to a gross necropsy examination. The necropsy consisted of an external examination, including reference to all clinically-recorded lesions, as well as a detailed internal examination.
Single intranasal administration of 5-MeO-DMT at the dose levels up to 75mg/kg was tolerated. There was no mortality and gross pathology findings at any dose. Body weight gain was slightly suppressed females at 75mg/kg. A range of clinical signs were observed and included incoordination, shallow or increased respiration, sneezing, salivation, decreased activity, piloerection, white pasty material around penis (for males), ptosis, laying on the cage floor, and sensitive to touch and shaking. The incidence and severity of these findings evolved as a function of the administered dose and were transient, with most being resolved within 1-hour post dose. Based on the clinical signs and maximal feasible volume/dose, 75mg/kg was judged to be the MTD, and this dose was selected for Phase 2.
During Phase 2, assessments of mortality, clinical signs and body weights were performed. Following dosing, all animals were euthanized and subjected to a necropsy examination on Day 8. The necropsy consisted of an external examination, including reference to all clinically-recorded lesions, as well as a detailed internal examination. Study plan specific tissues/organs were collected and retained, then trimmed and preserved promptly once the animal was euthanized but these were not further examined microscopically.
Intranasal administration of 5-MeO-DMT at 75mg/kg for 7 consecutive days was tolerated. There were no mortalities. Body weight gain was slightly suppressed for both sexes. Transient clinical signs similar to those of the Phase I included incoordination, mydriasis, increased or shallow respiration, gasping, sneezing, salivation, pale in colour, decreased activity, lying on the cage floor, piloerection, white pasty material around penis (for males), erect penis (for males), cold to touch, partially or completely closed eyes, sensitive to touch and shaking. These signs were generally less pronounced in terms of severity and incidence during the last few dosing days of this phase, and were resolved daily following dosing within 1-hour post administration. Macroscopic observations of note were limited to dark/pale area of the lungs in 2/10 animals; however, in the absence of histopathological examination, a possible test item-relationship of these findings could not be excluded. b. Maximum Tolerated Dose Followed by 7-Day Repeat-Dose Toxicology in Dogs (Study 62958)
The objectives of this study were to determine the maximum tolerated dose and the toxicity of the test item, 5- MeO-DMT (as the hydrochloride salt), following intranasal instillation in the dogs. In support of these objectives, the study consisted of 2 individual phases.
The test item was administered once by intranasal instillation to one male and female dog for up to 5 dose levels until the highest tolerable dose (MTD) was determined as described in Table 11.
Table 11: Doses Administered in the Dose Escalation Phase in Study 62958 a Each subsequent dose was administered following a washout period of minimum 3 days between doses. b Dose levels refer to the freebase of BPL-5MEO salt form. c Targeted dose concentrations were calculated based on an estimated body weight of 10 kg. d These animals were dosed at higher dose level of 5mg/kg.
There were no BPL-5MEO-related effects on mortality or bodyweights. Slight decreases in food intake were observed following administration for the male on Days 1 (Dose 1) and 9 (Dose 2) and for the female on Days 4 (Dose 1) and 9 (Dose 2). A range of clinical signs were observed and included gnawing cage wire, dilated pupils, changes in respiration, incoordination, decreased activity, vocalization, salivation, erect penis (for males) and shaking. After the last escalating dose at 3.5mg/kg/day, the male animal presented a convulsion shortly after dosing which lasted for 8 minutes. All clinical signs disappeared within an hour after the dosing except for decreased activity, dilated pupils and lying on the cage floor which were present on few occasions at 1-hour post dose or a few minutes after. The MTD for the test item was considered to be 2.5mg/kg.
In the phase 2 (dose confirmation), BPL-5MEO was administered at the MTD to one male and female dog once daily by intranasal instillation for 5 consecutive days and then twice daily on Days 6 and 7 (minimum 4 hours apart). During Phase 2, assessments of mortality, clinical signs, body weights and food consumption were performed. A series of blood samples were collected on Days 1 and 7 for determination of plasma concentrations of 5-MeO-DMT using an LC/MS/MS method. Following the last dosing, all animals were euthanized and subjected to a necropsy examination on Day 8. The necropsy consisted of an external examination; including reference to all clinically-recorded lesions, as well as a detailed internal examination. Study plan specific tissues/organs were collected and preserved following necropsy but were not further examined microscopically.
There were no test item-related effects on mortality or bodyweights. Slight decreases in food intake were observed for the male animal on Day 7 and for the female animal on Days 5 and 7. A range of clinical signs were observed and included muscle stiffness, gnawing cage wire, dilated pupils, changes in respiration, decreased activity, incoordination, vocalization, salivation, erect penis (for the male) and shaking. All clinical signs disappeared within an hour after the dosing except for decreased activity, dilated pupils, and lying on the cage floor which were present on few occasions at 1-hour post dose or a few minutes after. All observations were considered transient.
Toxicokinetic assessments were performed on Days 1 and 7; the maximum BPL-5MEO plasma concentration (Cmax) ranged from 541 to 803 ng/mL and was reached (Tmax) within 2 to 15 minutes post dose in both sexes. Dose normalized AUCs ranged from 2980 to 7320 min*kg*ng/mL/mg in both sexes. After Tmax, BPL-5MEO plasma concentrations declined at an estimated ti/2from 19.1 to 34 minutes in both sexes. There were no sex differences in any of the measured toxicokinetic parameters on either occasion. Over the 7-day treatment period, BPL-5MEO did not accumulate when administered daily by intranasal instillation.
2. Pivotal Studies a. A 14-Day Repeat-Dose Intranasal Toxicity Study Followed by a 14-Day Recovery Period in Rats (Study 700041)
The objective of this GLP study was to determine the toxicity and toxicokinetic (TK) profile of BPL-5MEO following intranasal instillation in Sprague Dawley rats for 14 consecutive days and to assess the persistence, delayed onset, or reversibility of any changes following a 14-day recovery period.
BPL-5MEO and control/vehicle were administered to groups of rats once daily by intranasal instillation for 14 consecutive days as described in Table 12.
Table 12: Doses Administered in 14-Day Repeat Dose Study in Rats a Vehicle control animals were administered 0.1% Hydroxypropyl methyl cellulose (HPMC) in water, b Nominal dose levels refer to the freebase of 5-MeO-DMT salt form. c The dose volume administered to each animal was 75 pL/kg/nostril. d Dose volume was not to exceed 25 pL/nostril for all animals regardless of their bodyweight.
The animals were monitored for mortality, clinical signs, respiratory measurements, body weights, food consumption, and body temperature. Ophthalmoscopic examinations and respiratory function tests were performed on all animals at scheduled timepoints. Clinical pathology assessments (hematology, coagulation, clinical chemistry, and urinalysis) were evaluated at termination. Blood samples were collected from the jugular vein from the TK animals on Days 1 and 14, for up to 8 hours after treatment for bioanalysis of 5-MeO-DMT concentrations in plasma and the subsequent calculation of toxicokinetic parameters. Following dosing, the Main animals were euthanized and subjected to a complete necropsy examination on Day 15. The Recovery animals were observed for an additional 14 days and then euthanized and subjected to a complete necropsy examination on Day 28. TK animals were euthanized after the last blood collection and discarded without further examination. At terminal euthanasia, selected tissues/organs were weighed, and microscopic evaluations of a standard set of tissues including the nasal turbinates (4 sections) and brain (7 sections) were performed for all Main and Recovery study animals.
Following dosing, animals in the Main group were euthanized and subjected to a necropsy examination on Day 15. The animals in the Recovery group were observed for 14 days and then euthanized and subjected to a necropsy examination on Day 28. For toxicokinetics, a series of 8 blood samples (approximately 0.5mL each) were collected from all rats in the Toxicokinetic group (3 rats/sex/timepoint) on Days 1 and 14 of the treatment period at 2, 5, 10, 15 and 30 minutes, and 1.0, 3.0 and 8 hours after treatment. For control rats (3 rats/sex) in the Toxicokinetic group only 1 sample was collected at the 15 minutes post dosing timepoint on Days 1 and 14.
Toxicity was based on the following parameters monitored: mortality/morbidity, clinical observations, body weights/gains, food consumption, ophthalmoscopy, clinical pathology (hematology, coagulation, chemistry, and urinalysis), necropsy observations, selected organ weights, and microscopic examination of a complete set of standard tissues including 4 cross levels of the nasal cavity and 7 sections of the brain.
Results
All the samples met the acceptance criteria for accuracy (100 ± 10% of their nominal concentration).
All animals were dosed without any major incidents and no sneezing was noted. All groups received their targeted doses on Days 1 to 10. As the maximum feasible loading dose was not to exceed 25 pL/naris (due to limited nasal surface area), once the bodyweights exceeded 333 g, male animals in all groups received slightly lower dose levels on Days 11 to 14. This was considered to have no impact on the study data as the differences were negligible.
No mortality occurred over the course of this study.
The observed clinical signs were as follows:
Group 2 (Low Dose)
Both male and female animals exhibited incoordination, shaking, salivation, decreased activity, lying on cage floor and sensitive to touch. For one female animal on Day 3, increased respiration was also observed.
Both male and female animals exhibited incoordination, shaking (or tremor), increased or shallow respiration, mydriasis, salivation, decreased activity, partially closed eyes, lying on cage floor and sensitive to touch. Male animals also exhibited erect penis.
Both male and female animals exhibited incoordination, shaking (or tremor), increased or shallow respiration, mydriasis, salivation, decreased activity, partially closed eyes, lying on cage floor and sensitive to touch. Male animals also exhibited erect penis.
Increased respiration was recorded for the mid and high dose group, however, measured respiratory values using plethysmographs proved that there were actually decreases in respiratory rates.
All the above clinical signs were considered to be transient for all groups.
Slight, generally dose-dependent body weight gain suppression was observed for both sexes between Days 1 to 14. There were no changes in food consumption that could be attributed to treatment with at dose levels <75mg/kg/day for 14 days.
On Day 14, slight body temperature increases were observed at 15 minutes and 30 minutes postdose for all treated male animals, for females on Day 14, the body temperature increases were observed in one or all treated groups for all the timepoints (until 2 hours postdose). These increases in body temperature were more pronounced in the mid (20mg/kg/day) and high (75mg/kg/day) dose groups.
When compared to pretreatment or control group, decreases in respiratory rates were observed at 20 minutes postdose timepoint which resulted in decreases in respiratory minute volumes. Tidal volume values were either comparable to pre-dose or to control values. The 20-minute postdose respiratory measurements on Day 1 was not performed for Group 2 female animals inadvertently. This considered to have no impact on the study data as the data could be extrapolated form the male animals in the same group. There were no significant between the sexes.
There was no adverse ocular effect, caused by the administration of BPL-5MEO at dose levels <75mg/kg/day for 14 days.
All other clinical observations, bodyweight changes, food consumption changes, and body temperature changes were considered to be not BPL-5MEO-related as they were sporadic, comparable to pretreatment signs or control animals, and not dose-related.
When compared to control Group, platelet, neutrophil, monocyte and basophil counts were slightly increased in mid and high dose groups in both sexes, however, these values were still within the historical ranges. On Day 28, all these values were compared to those in control group.
All changes in the hematology parameters, including those that reached statistical significance, were not attributed to the administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and/or not dose-related.
When compared to control Group, activated partial thromboplastin times (APTT) were increased for both sexes in the mid (20mg/kg/day) and high (75mg/kg/day) dose groups. All the coagulation values on Day 28 were comparable to control group. All other changes in the coagulation parameters were not attributed to the administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and/or not dose-related.
There were no changes in clinical chemistry and urinalysis parameters that could be attributed to the administration of BPL-5MEO at dose levels <75mg/kg/day for 14 days. All changes in the parameters, including those clinical chemistry parameters that reached statistical significance, were not attributed to the administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and/or not dose-related.
Compared to control values, there were decreases in thymus weights (absolute and relative to terminal body weight) observed in male animals as shown in Table 13.
Table 13: Thymus Weights for Male Animals Compared to Control Group a For Control group, the organ weight in grams is reported, for other groups, the percentage compared to the control value is shown.
All changes in the organ weight parameters, including those that reached statistical significance, were not attributed to the administration of BPL-5MeO as they were minor, comparable to control values, and/or not dose related.
There were no macroscopic findings related to treatment with BPL-5MEO in rats in either the Main Recovery groups.
For animals in the Main group, microscopic findings related to treatment with BPL-5MEO, were noted in the nasal cavity sections 1, 2, 3 and 4 of Main rats. A range of minimal to mild changes were noted in the respiratory, transitional, and/or olfactory epithelium of the nasal cavities, 1, 2, 3, and 4. The incidence and severity of changes were greater in males compared to females and were proportional to the dose of BPL-5MEO.
Microscopic changes observed in rats dosed with 75mg/kg/day of BPL-5MEO (Group 4) included: respiratory epithelium, minimal to mild degeneration, hyperplasia, and squamous metaplasia, minimal mononuclear infiltrate and/or lumen exudate in nasal cavities 1, 2, 3, and/or 4; transitional epithelium, minimal hyperplasia in nasal cavity 1, and; olfactory epithelium, minimal to mild degeneration and/or minimal mononuclear infiltrate and erosion in nasal cavities 2, 3, and/or 4. Minimal degeneration of the olfactory epithelium of the nasal cavities 2 and 3 was noted in male and/or female rats dosed with 5 and/or 20mg/kg/day of BPL-5MEO (Group 2 and 3). Minimal degeneration of the respiratory epithelium of the nasal cavities 1 and 2 was noted in male and/or female rats dosed with 20mg/kg/day of BPL-5MEO (Group 3).
For animals in the Recovery group, microscopic findings related to treatment with BPL-5MEO, were noted in the nasal cavity sections 1, 2, 3, and 4 of Recovery rats. Minimal to mild changes were noted in the respiratory and olfactory epithelium of the nasal cavities, 1, 2, 3, and/or 4. The incidence and severity of changes were greater in males compared to females. Microscopic changes included minimal to mild degeneration of respiratory epithelium in nasal cavities 1 and 2 and minimal degeneration olfactory epithelium in nasal cavities 2, 3, and 4 indicating incomplete but progressive ongoing reversal of epithelial degeneration following a 14-day recovery period. There was complete reversal of all other microscopic changes noted previously in the nasal cavities of Main rats following a 14-day recovery period including reversal of epithelial hyperplasia, squamous metaplasia, mononuclear infiltrate, erosion, and lumen exudate.
Other microscopic findings in both the Main and Recovery groups were considered to be procedure-related or incidental as they were not dose-related, of low incidence or severity, and/or as they were also seen in the control animals.
Toxicokinetics
Over the dose range, exposure to 5-MeO-DMT (based on the area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration [AUCo-nast ] values) on Days 1 and 14 generally increased dose-dependently (except for Group 4 as stated below), but not consistently in a dose-proportional manner as some increases were more or less than dose-proportional between different doses. Furthermore, on Day 14, the exposure in Female group 4 (75mg/kg/day) decreased compared to Female Group 3 (20mg/kg/day).
The sex ratios ranged between 0.4 and 6.2, but as the sex ratio randomly varied between dose groups and occasions, it was considered there was no sex-related difference.
Accumulation ratios (based on AUCo- ast) ranged sporadically from 0.3 to 2.9 (Day 14/Dayl) suggesting that 5-MeO- DMT does not accumulate when administered once daily for 14 consecutive days (2 weeks) by intranasal instillation in the Sprague Dawley rats at doses up to 75mg/kg/days.
The mean toxicokinetic parameters for Groups 2, 3, and 4 are presented in Table 14.
Table 14: Mean Toxicokinetic Parameters From Study 700041
Abbreviations: AUCo-nast = Area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration; AUCiNF_obs = Area under the plasma drug concentration-time curve from the time of dosing extrapolated to infinity; Cmax = The maximum plasma concentration; h = hours; SE = standard error of mean; ti/2 = Terminal elimination half-life; Tmax = Time to maximum plasma concentration.
Conclusion
Intranasal administration of BPL-5MEO at dose levels <75mg/kg/day for 14 consecutive days was tolerated with no BPL-5MEO-related effects on mortality, ophthalmology, clinical chemistry, macroscopic findings and urinalysis. Slight dose-dependent body weight gain suppression was observed for both sexes. Transient clinical signs included incoordination, shaking (or tremor), increased or shallow respiration, mydriasis, salivation, decreased activity, partially closed eyes, lying on cage floor and sensitive to touch. Male animals also exhibited erect penis. Slight dose dependent body temperature increases were observed for both sexes.
Decreases in respiratory rates were observed at 20 minutes post dose timepoint which resulted in decreases in respiratory minute volumes. Platelet, neutrophil, monocyte and basophil counts were slightly increased in mid and high dose groups in both sexes. APTT were increased for both sexes for main animals in the mid (20mg/kg/day) and high (75mg/kg/day) dose groups. There were decreases in thymus weights (absolute and relative to terminal bodyweight) observed in male animals. Microscopic changes were noted in nasal cavities 1, 2, 3, and/or 4 involving the respiratory, olfactory, and transitional epithelium. The incidence and severity of findings were greater in males compared to females and were proportional to the dose of BPL-5MEO with incomplete but progressive on-going reversal following a 14-day recovery period.
The NOAEL was reported as the lowest dose of 5mg/kg. b. A 14-Day Repeat-Dose Intranasal Toxicity Study Followed by a 14-Day Recovery Period in Dogs (Study 62959)
The objective of this GLP study (Study 62959) was to determine the toxicity and TK profile of BPL-5MEO following intranasal instillation in Beagle dogs for 14 consecutive days and to assess the persistence, delayed onset, or reversibility of any changes following a 14-day recovery period.
BPL-5MEO and control/vehicle were administered to groups of dogs once daily by intranasal instillation for 14 consecutive days as described in Table 15.
Table 15: Doses Administered in 14-Day Repeat Dose Study in Dogs a Vehicle control animals were administered 0.1% Hydroxypropyl methyl cellulose (HPMC) in water. b Dose levels refer to the freebase of 5-MeO-DMT salt form. c Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 at the dose level of 2.5mg/kg. The dose level was subsequently decreased on Day 1 for the Replicates B and C to 1.5mg/kg. Replicate A received 1.5mg/kg on Days 2 to 14. d The dose volume administered to each animal was 10 pL/kg/nostril. e Dose volume was not to exceed 100 pL/nostril for all animals regardless of their bodyweight. Assessments of mortality, clinical signs, olfactory reflex, body weights, food consumption, ophthalmology, and electrocardiograms were performed. In addition, clinical pathology assessments (hematology, coagulation, clinical chemistry and urinalysis) were evaluated once pretreatment and at termination. Blood samples were collected from the jugular vein of all animals on Days 1 and 14, at up to 8 time points relative to treatment, for analysis of test item concentration in plasma and the subsequent calculation of toxicokinetic parameters. Following dosing, the Main animals were euthanized and subjected to a complete necropsy examination on Day 15. The Recovery animals were observed for an additional 14 days test article free and then euthanized and subjected to a complete necropsy examination on Day 28. All Main and Recovery study animals underwent complete necropsy examinations, selected tissues/organs were retained, and microscopic evaluations of a standard set of tissues were performed.
For toxicokinetics, a series of 8 blood samples were collected from the jugular vein from all treated animals on each of Days 1 and 14 of the treatment period at 2, 5, 10, 15, 30, and 60 minutes as well as 3 and 8 hours after treatment. For Group 1, only one sample was taken at 15 minutes post dosing on Days 1 and 14 in order to confirm the absence of BPL-5MEO in animals in the vehicle control group. Blood samples were analysed for the BPL-5MEO concentration in plasma and the subsequent calculation of TK parameters.
Results
All the dose formulation samples collected and analysed met the acceptance criteria for accuracy (100 ± 10% of their nominal concentration).
Daily intranasal administration of BPL-5MEO to both nostrils of Beagle dogs once daily for 14 consecutive days at dose levels up to 1.5mg/kg/day did not cause any mortality. High dose animals initially given to a subset of dogs at 2.5mg/kg and showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 and this dose exceeded the MTD. The high dose was subsequently lowered on Day 2 to 1.5mg/kg/day and this dose was tolerated. Animals in all treated Groups exhibited transient clinical observation of incoordination, vocalization, mydriasis, decreased or increased activity, increased respiration, gnawing cage wire, excessive licking of nose or lips and circling. In addition, eye discharge and shaking were observed in the Mid and High dose groups. Erect penis was also recorded for the high dose male animals. All these clinical signs were considered to be exacerbated pharmacology manifestations, occurred within 10 to 30 minutes of dosing, and were resolved within 90 minutes.
When compared to control Group, the triglyceride level of 1/3 Group 3 female, 1/5 Group 4 male and 4/5 Group 4 females were increased, these data are presented in Table 16. There were no other treatment-related clinical pathology findings.
Table 16: Mean ± SD Day 14 Triglyceride Values Compared to Control Group
Abbreviations: SD = standard deviation a' for Control group, the control value is mentioned, for other groups, the percentage compared to the control value is shown. b Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 at the dose level of 2.5mg/kg. The dose level was subsequently decreased on Day 1 for the Replicates B and C to 1.5mg/kg. Replicate A received 1.5mg/kg on Days 2 to 14.
All other changes in the clinical chemistry parameters, including those that reached statistical significance, were not attributed to the administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and/or not dose related.
There were no changes in olfactory reflex, food consumption, body weight, ocular effect, or ECG that could be clearly attributed to treatment with BPL-5MEO at a dose level <1.5mg/kg/day for 14 days. All body weight changes were not attributed to the administration of the test item as they were minor, and not toxicologically relevant. All food consumption changes, including those that were statistically significant, were not attributed to the administration of the test item as they were minor, and not toxicologically relevant.
Animals showed hyperthermia at the dose level of 2.5mg/kg/day on Day 1. Transient body temperature increases were observed on Day 14 for high dose group in both sexes at 15 and 30 minutes postdose. All other body temperature changes were not attributed to the administration of the test item as they were minor, and not toxicologically relevant.
Histopathological examination results for Main animals included minimal to moderate decreased cel lularity of the thymic lymphocytes at dose levels of 0.8 (1 male) and 1.5mg/kg/day (3 males), which was determined as stress related. Minimal epithelial metaplasia of respiratory epithelium in the nasal cavities found at dose levels of 0.8 (1 female) and 1.5mg/kg/day (2 males) and minimal to mild mononuclear cell infiltrate of the olfactory epithelium in the nasal cavities seen at a dose level of 1.5mg/kg/day (1 male/1 female) were considered to be signs of irritation caused by BPL-5MEO but not adverse.
In animals euthanized after a 14-day recovery period, only minimal mononuclear cell infiltrate of the olfactory epithelium in the nasal cavities was still present at a dose level of 1.5mg/kg/day (1 female) but at a lower severity when compared with animals euthanized terminally, indicative of recovery. Decreased cellularity of thymic lymphocytes was no longer observed.
Toxicokinetics
BPL-5MEO was not detected in any of the samples collected from the Control (Group 1) animals on Days 1 and 14.
The mean toxicokinetic parameters for Groups 2, 3, and 4 are presented in the table below.
Mean Toxicokinetic Parameters From Study 62959
Abbreviations: AUCo-nast = Area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration; AUCiNF_obs = Area under the plasma drug concentration-time curve from the time of dosing extrapolated to infinity; Cmax = The maximum plasma concentration; h = hours; ti/2 = Terminal elimination half-life; Tmax = Time to maximum plasma concentration. a Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 at the dose level of 2.5mg/kg. The dose level was subsequently decreased on Day 1 for the Replicates B and C to 1.5mg/kg. Replicate A received 1.5mg/kg on Days 2 to 14.
Over the dose range, exposure to BPL-5MEO (based on AUCo-nast values) on Days 1 and 14 generally increased dose- dependently (except for Group 4 as stated below), but not consistently in a dose-proportional manner as some increases were more or less than dose-proportional between different doses. Furthermore, on Day 14, the exposure in Group 4 (1.5mg/kg/day) decreased compared to Group 3 (0.8mg/kg/day). There were no marked sex-related differences in any of the measured toxicokinetic parameters, except on Day 14 where Tmax occurred slightly later in Group 4 males as compared to Group 4 females. The sex ratios (male/female), with the exception of Group 4 Tmax, ranged sporadically from 0.5 to 1.7 on Days 1 and 14.
Accumulation ratios (based on AUCo-nast) ranged sporadically from 0.6 to 2.0 (Day 14/Dayl) suggesting that BPL-5MEO does not accumulate when administered once daily for 14 consecutive days (2 weeks) by intranasal instillation in beagle dogs at doses up to 1.5mg/kg/day.
Conclusion
Based on the parameters examined where all the changes noted were considered either non-adverse or related to exaggerated pharmacological effects, the reported NOAEL for BPL-5MEO, when dosed for 14 consecutive days by intranasal administration, followed by a 14-day recovery period was considered to be 1.5mg/kg/day, corresponding of 213 (220) h*ng/mL (combined for both sexes).
Toxicokinetic Considerations
Based on preliminary data from another ongoing study in dogs, it has been observed that the site of blood sampling in dogs may impact the measured plasma exposure. Samples from the jugular vein may result in higher apparent exposure levels than samples from the cephalic vein, which might be due to the local transmucosal route of administration (also reported in the scientific literature (Ilium, 2003; Sohlberg, 2013)). Therefore, dose escalation criteria for the Phase 1 Single Ascending Dose study are based on assessment of clinical criteria, safety factors and exposure. A maximum dose of 14mg has been designated. The Table below summarizes the clinical observations in the rat and dog toxicity studies performed with BPL-5MEO. These clinical signs are considered to be related to the pharmacological activity of BPL-5MEO and demonstrate a dose-related increase in severity of findings on both species, generally ranging from mild to moderate at 0.4 to 1.5mg/kg in dogs and 1.5 to 5mg/kg in rats.
Summary of Clinical Observations in Applicant-Sponsored Animal Studies
Abbreviations: HED = Human Equivalent Dose (for a 60 kg human) a = NOAEL determined in the 14-day toxicology studies for both species. b = Preliminary data, ongoing study (Slight tremor was observed at l.Omg/kg = 33mg HED)
Note: these signs were of short duration, and generally resolved within one to two hours in both species.
Example 14: Genotoxicity
The genotoxicity potential of 5-MeO-DMT was evaluated in silico (computational analysis) for structural alerts and in vitro in GLP assays to assess mutagenic and clastogenic potential following the ICH S2 ( Rl) Guidance.
In Silico
5-MeO-DMT, its primary active metabolite, bufotenine, and an identified drug substance impurity, MW234, were evaluated for quantitative structural activity relationships for potential mutagenicity and/or carcinogenicity using two computation analytical methods, Derek Nexus and the Leadscope Genetox Statistical Models. The evaluation from both analyses did not identify any structural alerts associated with 5-MeO-DMT or bufotenine, and a possible nor an identified drug substance impurity MW234.
In Vitro Mutagenicity
The mutagenic potential of 5-MeO-DMT was evaluated in a GLP Bacterial Reverse Mutation Test (Ames test) for the ability to induce reverse mutations at selected loci of Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537 and the Escherichia coll tester strain WP2uvrA. These strains were treated with 5-MeO-DMT at concentrations of 1.6, 5, 16, 50, 160, 500, 1600 and 5000 pg per plate along with the vehicle/negative and appropriate positive controls. The assay was performed in triplicate using the pre-incubation method in the absence and presence of an exogenous metabolic activation system, phenobarbital/5,6-benzoflavone-induced rat liver 59 microsomal enzyme mix (59 mix)
A slight cytotoxicity was seen at the concentration of 1600 pg/plate in all S. typhimurium strains. Although higher levels of cytotoxicity were observed at 5000 pg/plate in the absence of 59 mix, it remained slight in the presence of 59 mix in these strains. No cytotoxicity was noted in the E. coll strain in either the absence or presence of 59 mix.
Overall, no increases (>2x of the vehicle/negative values) in the number of revertant colonies per plate was observed with 5-MeO-DMT in S. typhimurium tester strains TA1535, TA100, E. coll \NP2uvrA in either the absence and presence of 59 or with TA1537 and TA98 in the presence of 59 mix. Three exceptions were a 2.1-fold increase at 1600 pg/plate without 59 seen in E. coli WP2uvrA, a 2.0-fold increase in S. typhimurium TA1537 at 50 pg/plate with 59, and 2.1-fold increase in S. typhimurium TA1535at 1600 pg/plate with 59. However, these values were not considered biologically relevant as the values were within laboratory's historical vehicle/negative control range and were not dose-related.
Two of the 5-MeO-DMT-treated S. typhimurium strains, TA1537 and TA98, in the absence of 59 mix, showed a number of revertant colony counts slightly higher than twice of the vehicle/negative values at 160 pg/plate and 500 pg/plate with fold-increases at 2.3- and 2.7-fold in TA1537 and 2.2- and 2.4-fold in TA98. The increased colony counts observed in these strains were still within the laboratory's historical vehicle/negative control range and were not overall dose-related; therefore, they did not meet the criteria of positive results. However, as the increases were seen in TA98 and TA1537 in 2 adjacent dose levels and that 2 strains showed a similar trend of increases in revertant colony counts at the same concentration levels, the results were judged equivocal. Therefore, the bacterial reverse mutation test was repeated in the absence of 59 mix for these 2 strains in order to investigate these equivocal results. The repeat test used a narrower concentration range of 15, 30, 60, 120, 250, 500, 1000, and 2000 pg per plate. The results from repeated test showed no increases in the revertant colonies number per plate for both 5- MeO-DMT-treated strains in all concentration levels tested up to the maximal dose of 2000 pg/plate. Therefore, it was concluded that the small increases observed in the first test for S. typhimurium tester stains TA 1537 and TA98 were not biologically relevant.
In conclusion, the results of the bacterial reverse mutation assays indicated that 5-MeO-DMT did not induce any increase in revertant colony numbers with any of the bacteria strains tested either in the absence or presence of the rat liver 59 microsomal metabolic activation system. 5-MeO-DMT has no mutagenic potential in the bacterial reverse mutation test. The expected response of the positive and negative controls affirmed the sensitivity and validity of assay. In Vitro Clastogenicity
The clastogenic potential of 5-MeO-DMT was evaluated in a GLP in vitro micronucleus test using Chinese hamster ovary (CHO)-Kl cells using flow cytometry. Exponentially growing cells were treated in duplicate with the 5-MeO- DMT at 9 concentrations up to the recommended upper limit of 1 mM (corresponding to approximately 300 pg/mL): 1.25, 2.5, 5.0, 10, 20, 40, 80, 150 and 300 pg/mL. The treatment with the vehicle/negative and positive controls was concurrently performed. There were 3 treatment regimens: a 4-hour-short exposure in either absence or presence of an exogenous metabolic activation system, phenobarbital/5,6 benzoflavone rat liver 59 microsomal enzyme mix (59 mix), and a 26 hour-extended exposure, considered a confirmatory phase, in the absence of 59 mix.
No cytotoxicity or precipitation was observed in 5-MeO-DMT-treated cells up to the maximal dose level of 300 pg/mL throughout the treatment periods. In all treatment regimens, the results of the in vitro micronucleus test indicate that 5-MeO-DMT did not induce any increases in micronuclei or hypodiploid cells either in the absence or presence of the rat liver 59 microsomal metabolic activation system. In conclusion, 5-MeO-DMT showed no chromosome-damaging potential in the in vitro micronucleus test with CHO-K1 cells. The expected response of the positive and negative controls affirmed the sensitivity and validity of assay.
Reproductive and Development Toxicity
Reproductive and developmental toxicity studies have not been conducted. In the 14-day pivotal GLP intranasal toxicity studies in rats and dogs, there was no evidence of an adverse effect on reproductive tissues with systemic exposure to BPL-5MEO.
Example 15: Formulation
BPL-5MEO has been synthesised to Good Manufacturing Practice (GMP) standards and prefilled into the Aptar Unidose Intranasal Liquid Delivery System device. The device allows a single fixed dose of BPL-5MEO to be administered intranasally. The liquid is prefilled into and administered using a standard single unit dose nasal pump device. Excipients used in the formulation are water, 0.1% hydroxypropyl methylcellulose (HPMC) and sodium hydroxyl (NaOH). Two concentrations of the formulation will be used, 70mg/mL (for dose levels below 7mg), and 140mg/mL (for dose levels above 7mg).
In an embodiment, there is provided a composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
70mg/ml 5-MeO-DMT.
In an embodiment, there is provided a composition comprising 5-MeO-DMT benzoate, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
70mg/ml 5-MeO-DMT.
In an embodiment, there is provided a composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
140mg/ml 5-MeO-DMT.
In an embodiment, there is provided a composition comprising 5-MeO-DMT benzoate, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC); 0.1% sodium hydroxyl (NaOH); and
140mg/ml 5-MeO-DMT.
In an embodiment, there is provided an intranasal composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
70mg/ml 5-MeO-DMT.
In an embodiment, there is provided an intranasal composition comprising 5-MeO-DMT benzoate, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
- 70mg/ml 5-MeO-DMT.
In an embodiment, there is provided an intranasal composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
140mg/ml 5-MeO-DMT.
In an embodiment, there is provided an intranasal composition comprising 5-MeO-DMT benzoate, wherein the water;
0.1% hydroxypropyl methylcellulose (HPMC);
0.1% sodium hydroxyl (NaOH); and
140mg/ml 5-MeO-DMT.
In an embodiment, the composition comprises 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25- 50mg/mL; 50-400mg/mL; 50-300mg/mL; 60-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200- 300mg/mL; 200-400mg/mL; 30-100mg/mL; 300-400mg/mL; 300-500mg/mL; 45-75mg/mL; 50-70mg/mL; 55- 65mg/mL; or 50-60mg/mL 5-MeO-DMT.
In an embodiment, there is provided an intranasal liquid delivery system comprising a composition of 5-MeO-DMT. In an embodiment, there is provided a single unit dose capsule of a composition of 5-MeO-DMT. In an embodiment, there is provided an intranasal composition comprising a dosage amount 50-150mg/ml 5-MeO-DMT in a liquid medium, wherein the 5-MeO-DMT is formulated as the benzoate salt of 5-MeO-DMT (5-MeO-DMT benzoate). In an embodiment, 5-MeO-DMT benzoate is present as a suspension or emulsion in the liquid medium.
In an embodiment, there is provided an intranasal liquid delivery system comprising:
70 to 140mg/ml of 5-MeO-DMT benzoate as a suspension or emulsion in a liquid medium.
Example 16: Administration
BPL-5MEO is administered to subjects by a trained member of the research team using a single unit dose pump spray. The unit contains only 1 spray, so should not be tested before use. While sitting down the subject is asked to blow their nose to clear the nasal passages. Once the tip of the device is placed into the nostril the clinic staff will press the plunger to release the dose.
In an embodiment, there is provided a method for the administration of 5-MeO-DMT comprising administering the 5-MeO-DMT as an intranasal spray to a human subject wherein the human subject has followed patient preparation parameters that include blowing their nose to clear their nasal passages immediately prior to administration. In an embodiment, the human subject is seated.
In an embodiment, there is provided a method for the delivery of 5-MeO-DMT to the brain of a human subject comprising administering the 5-MeO-DMT as an intranasal spray to a human subject wherein the human subject has followed patient preparation parameters that include blowing their nose to clear their nasal passages immediately prior to administration.
Example 17: X-Ray Powder Diffraction (XRPD) of 5-MeO-DMT benzoate
The XRPD pattern of 5-MeO-DMT benzoate salt, was acquired before and following particle size reduction with a mortar and pestle. This reduced the intensity of dominant diffractions and revealed that the XRPD pattern of the benzoate salt was prone to preferred orientation prior to particle size reduction, which is a function of the habit and particle size of the material. XRPD patterns of the benzoate salt prior to and following particle size reduction can be seen in Figures 6 and 7 respectively. The XRPD patterns of the benzoate salt prior to and following particle size reduction overlaid on one another can be seen in Figure 8.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.3°20. In an embodiment, there is provided crystalline 5- MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5,
17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO- DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0,
22.7, 24.7, 25.3 and 3O.5°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figures 6, 7 or 8. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 6. In an embodiment, there is provided crystalline 5- MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 7. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 8.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of:
Peaks in an XRPD diffractogram as previously or subsequently described;
An endothermic event in a DSC thermograph as previously or subsequently described;
An onset of decomposition in a TGA thermograph as previously or subsequently described;
A DVS isotherm profile as previously or subsequently described; and A crystalline structure as previously or subsequently described.
Example 18: Thermal analysis of 5-MeO-DMT benzoate
The differential scanning calorimetry (DSC) thermograph of 5-MeO-DMT benzoate salt, contained one endotherm with an onset of 123.34°C, peak of 124.47°C and an enthalpy of 134.72J/g. There were no other thermal events. The DSC thermograph, acquired at 10°C/min, can be seen in Figure 9.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C as substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C as substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of 123°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of 123°C a substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of 124°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of 124°C as substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C and a peak of between 122 and 128°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C and a peak of between 122 and 128°C as substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C and a peak of between 124 and 126°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C and a peak of between 124 and 126°C as substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g as substantially illustrated in Figure 9. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -135J/g. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -135J/g as substantially illustrated in Figure 9. The thermogravimetric analysis (TGA) thermograph of 5-MeO-DMT benzoate salt, revealed that the onset of decomposition was ca 131°C, which is past the melt at ca 125°C. The TGA thermograph, acquired at 10°C/min, can be seen in Figure 10. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an onset of decomposition in a TGA thermograph of 131°C. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C; and an onset of decomposition in a TGA thermograph of 131°C.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C and a peak of between 124 and 126°C; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C and a peak of between 124 and 126°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C; and an onset of decomposition in a TGA thermograph of 131°C.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C, a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C, a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C and an enthalpy of -135°C; and an onset of decomposition in a TGA thermograph of 131°C.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C and an enthalpy of -135°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10.
A combined TGA/DSC thermograph, acquired at 10°C/min, can be seen in Figure 11.
Example 19: Dynamic Vapour Sorption (DVS) of 5-MeO-DMT benzoate
The DVS profile for 5-MeO-DMT benzoate salt, revealed reversible water uptake/loss over the humidity range and no hysteresis. The water uptake/loss from 0 to 90% was gradual and amounted to a maximum of ca 0.20% and was a consequence of wetting of the solid. There was no evidence of form/version modification as a consequence of exposure of 5-MeO-DMT benzoate salt to variable humidity. The DVS isotherm can be seen in Figure 12.
The DVS isotherm of a 5-MeO-DMT Hydrochloride, lot 20/20/126-FP (Figure 17) was found to undergo significant moisture uptake upon the first sorption cycle from 70%RH. Approximately 23%w/w uptake is observed between 70- 80%RH, whereas less than 0.3%w/w moisture uptake from 0-70%RH was observed. A further 20%w/w moisture uptake is observed up to and when held at 90%RH before commencement of the second desorption cycle. Subsequent sorption and desorption cycles follow a similar profile with some observed hysteresis between operations that do not match the original desorption step. These return to ca. 6-9%w/w above the minimum mass recorded at 0%RH, which indicates significant retention of moisture. Upon completion of the DVS cycle, the input material was noted to have completed deliquesced.
A modified DVS isotherm of lot 20/45/006-FP (the same crystalline version) was undertaken to examine material behaviour from 60%RH and above. A 2 cycle DVS with desorption beginning from 40-0%RH with sorption from 0- 60%RH in 10%RH intervals, followed by incremental 5%RH increases to 65, 70, 75, 80 and finally 85%RH. This is to obtain in-depth profiling of the material towards humidity at these elevated levels. No significant moisture uptake/loss in first desorption-sorption profile between 0-70%RH was noted (Figure 18) followed by a ca. 0.46%w/w increase from 70-75%RH. A further ca. 7% uptake is observed from 75-80%RH, then ca. 40% from 80-85%w/w. Complete deliquescence of the solids was observed upon isolation of the material post DVS analysis, which has likely occurred above 80%RH. Temperature and humidity are important factors in the processing and storage of pharmaceuticals. DVS provides a versatile and sensitive technique for evaluating the stability of pharmaceutical formulations. The DVS profiles show that the stability of the benzoate salt of 5-MeO-DMT is significantly higher than that of the hydrochloride salt and is therefore a more promising salt for development as a pharmaceutical composition.
There is thus provided in an embodiment of the invention an increased stability composition of 5-MeO-DMT wherein the composition comprises the benzoate salt. There is further provided a composition of 5-MeO-DMT having an increased stability wherein the composition comprises the benzoate salt. In an embodiment, there is thus provided a pharmaceutical composition of 5-MeO-DMT benzoate having an increased shelf-life compared to a pharmaceutical composition of 5-MeO-DMT hydrochloride. In an embodiment, there pharmaceutical composition may be a nasal inhalation composition. It is advantageous that the 5-MeO-DMT benzoate salt retains a low/consistent moisture content over its shelf-life preserving its ability to be consistently formulated, and preserving its ability to be inhaled in a free flowing powder form. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by a DVS isotherm profile as substantially illustrated in Figure 12.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C, optionally a peak of between 124 and 126°C and optionally an enthalpy of between -130 and -140J/g as substantially illustrated in Figure 9; an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10; and a DVS isotherm profile as substantially illustrated in Figure 12.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, optionally a peak of 124°C and optionally an enthalpy of -135°C as substantially illustrated in Figure 9; an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10; and a DVS isotherm profile as substantially illustrated in Figure 12.
In an embodiment, any form of the 5-MeO-DMT salt is the hydrochloride salt where the hydrochloride is characterized by one or more of: peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°20±O.1°20; peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20±O.1°20; peaks in an XRPD diffractogram at 9.2, 12.2, 13.7, 14.1, 15.0, 18.5, 19.0, 19.5, 21.2, 23.3, 23.9, 24.5, 25.1, 26.0, 26.9, 27.5, 28.3, 29.0, 30.9 and 31.1°20±O.1°20 as measured by X-ray powder diffraction using an x- ray wavelength of 1.5406 A.; endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and/or a peak of between 142 and 148°C; enthalpy in a DSC thermograph of between 113J/g and -123J/g; onset of decomposition in a TGA thermograph of between 120 and 165°C.
In an embodiment, the peaks in an XRPD diffractogram may be at determined ± O.l°20, ± O.2°20 or ± O.3°20. It is considered that within the scope of the invention/disclosure, any numbers expressed to two decimal places can be rounded to one decimal place or to whole numbers. The person skilled in the art will appreciate the defining characteristics of one of more of the previously or subsequently described embodiments may be interchanged with those of one or more other embodiments.
Example 20: Microscopy, optical of 5-MeO-DMT benzoate
Optical microscopy examination was undertaken using an Olympus BX53M polarised light microscope and an Olympus SC50 digital video camera for image capture using imaging software Olympus Stream Basic, V2.4. The image scale bar was verified against an external graticule, 1.5/0.6/0.01 mm DIV, on a monthly basis. A small amount of each sample was placed onto a glass slide and dispersed using mineral dispersion oil if required. The samples were viewed with appropriate magnification and various images recorded. Optical micrographs of 5-MeO-DMT benzoate salt, were acquired. The material is composed of large rhombohedral/trigonal crystals, ranging from 400 to 1000 microns. There are also small crystals adhering to the large crystals. Some of the small crystals, from 10 microns, are a consequence of mechanical attrition, but others have formed by crystallisation. There are also large aggregates composed of various habits. Figures 13 to 16 show various optical micrographs of 5-MeO-DMT benzoate at various magnifications.
Example 21: Further characterisation of 5-MeO-DMT benzoate.
The propensity of 5-MeO-DMT benzoate to polymorphism was investigated and is considered low with solids isolated with two different XRPD patterns. The equilibration of 5-MeO-DMT benzoate in solvents with thermal modulation induced a form or version change which are not considered to be solvates. The anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate did not afford any solids indicating form or version change. The controlled cooling crystallisation investigation of 5-MeO-DMT benzoate did not afford any solids indicating form or version change. The reverse anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate did induce a form or version change.
Two versions of 5-MeO-DMT benzoate have been identified, the Pattern A form (see Example 17, hereafter this form is referred to as Pattern A) version and a second, Pattern B form, believed to be meta-stable. The equilibration investigation of 5-MeO-DMT benzoate in a range of solvents with thermal modulation returned Pattern A by XRPD from most solvents. The equilibration solvents toluene, chlorobenzene, and anisole induced a form or version change in the 5-MeO-DMT benzoate and is defined as Pattern B by XRPD. Solvate formation can be excluded based upon TGA. The anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate afforded solids which were concordant Pattern A by XRPD indicating no form or version change. The controlled cooling crystallisation investigation of 5-MeO-DMT benzoate afforded solids which were concordant Pattern A by XRPD indicating no form or version change. The reverse anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate returned Pattern A form from most mixtures. The methanoktoluene and IPA:toluene mixtures produced material which is considered to be Pattern B form with improved characteristics compared to the Pattern B form solids isolated via solvent equilibration.
XRPD examination (Figure 19) revealed a powder pattern of 5-MeO-DMT benzoate that was concordant with that found in previous XRPD examinations (see Example 17, Pattern A form). DSC examination (Figure 20) revealed one sharp endotherm with an onset of 122.95°C and a peak at 124.41°C which was a match with Pattern A form (see Example 18 wherein the onset is 123.34°C and the peak at 124.47°C). Additional XRPD examination of multiple lots of 5-MeO-DMT benzoate can be seen in Figure 21, matching Pattern A. DSC examination of 5-MeO-DMT benzoate lots Cl, DI and El revealed a common endothermic event with a peak temperature of 123.76°C to 123.88°C (Figure 22). TGA analysis of Cl, DI and El revealed a negligible weight loss before major decomposition (Figure 23). The XRPD patterns of Pl (Toluene), QI (Chlorobenzene), and R1 (Anisole) revealed a new diffraction pattern referred to as 'Pattern B'. These samples contained 3 common diffractions between 18.5 and 20° 20 (Figure 24). A selection of samples of Pattern A form: Cl (IPA:Heptane [1:1]), DI (3-Methyl-l-butanol:Heptane [1:1], and El (TBME) were thermally characterised. DSC examination of samples Pl, QI, and R1 revealed a major common endothermic event with a peak temperature of 123.73°C to 124.40°C and a minor common endothermic-exothermic event between 113.01 and 115.27°C. Sample R1 contained a unique endothermic event between the minor endothermic- exothermic event and the major endotherm with a peak temperature of 117.24°C. TGA examination revealed a negligible weight loss for samples Pl and QI. For sample R1 there was a weight reduction of 0.293% weight before decomposition. DSC thermographs of Pl, QI and R1 at 10°C.min 1 can be seen in Figure 25. DSC thermograph expansions of 5-MeO-DMT benzoate lots Pl, QI and R1 at 10°C.min 1 can be seen in Figure 26. TGA thermographs of 5-MeO-DMT benzoate lots Pl, QI and R1 at 10°C.min 1 can be seen in Figure 27.
XRPD examination of samples P2, Q2, and R2 (thermally cycled suspensions) revealed P2 and Q2 had converted to Pattern A form. However, R2 remained as Pattern B form but with larger diffractions concordant with Pattern B. The XRPD diffractogram of lots R1 and R2 (thermally cycled suspensions) compared with a reference Pattern A XRPD diffractogram can be seen in Figure 28. DSC examination of P2 revealed only the major endothermic event characteristic of the Pattern A form was present with a peak temperature of 124.48°C (Figures 29 -31). DSC revealed the minor endo-exotherm was smaller for sample Q2 with peak temperatures of 113.41 and 114.32°C but the major endotherm was unaffected with a peak temperature of 124.23°C (Figures 29 - 31). DSC examination of sample R2 revealed the endothermic event in the minor endo-exotherm had two peaks of 111.53 and 113.49°C followed by the exotherm with a peak temperature of 114.39°C, the minor events were much larger compared to R1 and the second minor endothermic event was not present (Figures 29 - 31). TGA examination revealed a negligible weight loss for samples P2 and Q2. For sample R2 there was a weight reduction of 0.583% before decomposition. The increase in weight loss corresponds to the increase in the magnitude of the minor events revealed by DSC (Figures 29 - 31).
The solvent mediated equilibration of 5-MeO-DMT benzoate with temperature modulation revealed the salt to be stable to version or form change except for the solvents toluene, chlorobenzene, and anisole. Solids isolated from these solvents had different XRPD patterns and thermal events indicating a version of form change of the salt. Solvate formation can be excluded based upon TGA. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate as described above.
Anti-solvent addition driven crystallisation of 5-MeO-DMT benzoate
Equilibration of Pattern A form in a variety of solvents and solvent mixtures with thermal modulation identified a range of potentially suitable solvents and anti-solvents. An investigation of the anti-solvent driven crystallisation of 5-MeO-DMT benzoate from solution was conducted. 5-MeO-DMT benzoate, 6 x 220mg, was dissolved in six solvents at 50°C (detailed in the Table below) and the stock solutions clarified through 0.45pm syringe filters. Aliquots of each solution containing 50mg of 5-MeO-DMT benzoate were charged to 4 crystallisation tubes. The THF and Acetonitrile solutions of 5-MeO-DMT benzoate crystallised post-clarification. All crystallisation tubes were heated to 55°C to afford solutions and cooled to 50°C. Samples were agitated via stirrer bead at 400rpm for the duration of the experiment. Various anti-solvents (detailed in the Table below), 2.5 vol., were charged to the solutions and the mixtures, then equilibrated at 50°C for 30 minutes and the anti-solvent addition repeated. The mixtures were cooled to 25°C over ca. 1.5 hours and equilibrated for 17 hours. Suspensions were isolated via isolutes and vacuum dried for 1 minute to remove excess solvent. The isolutes were transferred to a vacuum oven at 50°C for 24 hours.
The remaining solutions were heated to 50°C and anti-solvent, 5 vol. charged. The mixtures were equilibrated for 30 minutes and then repeated. Additional anti-solvent, 10 vol., was charged, equilibrated for 30 minutes, cooled to 25°C over 1.5 hours and equilibrated for 30 minutes. Suspensions were isolated via isolutes and vacuum dried to remove excess solvent and then dried in a vacuum oven at 50°C for 24 hours. The remaining solutions were reduced to ca. 0.25mL volume under N2 flow at 25°C. Anti-solvent, 20 vol., was charged and the mixtures equilibrated for 30 minutes. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate as described above.
Despite the initial suggestion that water was a potentially suitable anti-solvent, the utilisation of water as an antisolvent failed to afford suspensions. All THF, Acetone and MeCN containing mixtures (excluding water) afforded suspensions by cooling to 25°C with 10 volumes of anti-solvent. All other mixtures (excluding water) either required an increased anti-solvent charge or significant solution volume reduction and anti-solvent addition to afford suspensions. The XRPD examination of all isolated and dried solid samples were Pattern A as shown in Figures 32 and 33. The XRPD characterisation of the 5-MeO-DMT benzoate solids isolated from anti-solvent mediated crystallisation are concordant with Pattern A. This implies that there is no form/version modification of 5-MeO-DMT benzoate under the conditions investigated.
Controlled cooling crystallisation investigation of 5-MeO-DMT benzoate
Observations from both the initial equilibration investigation and the first anti-solvent based investigations of 5- MeO-DMT benzoate identified potentially suitable solvents for the dissolution of 5-MeO-DMT benzoate at temperature to afford saturated solutions that could then be subject to a controlled gradual cooling operation. 5- MeO-DMT benzoate, 25±0.5mg, was dissolved in the minimal volume of solvent at 50°C (detailed in the Table below). The solutions were clarified through a 0.45pm Teflon syringe filter into pre-heated crystallisation tubes and cooled from 50°C to -10°C over 60 hours (1°C Hr-1 cooling rate) and held at -10°C for 50 hours (no agitation). Several crystallisations contained large off-white crystals on the base of the crystallisation tube (detailed in the Table below). The crystals were directly transferred from the crystallisation tube to the XRPD sample holder and were left open to the atmosphere for ca. 1 hour prior to analysis. The remaining mixtures were agitated at 400rpm at ambient temperature, open to the atmosphere to allow partial solvent evaporation, over 18 hours.
XRPD examination of the solid samples isolated following cooling of the solutions (observed as relatively large particles) revealed evidence of preferred orientation (Figure 34). The particle size of the samples was reduced via particle size reduction with a mortar and pestle. Subsequent re-examination by XRPD revealed all solids to be Pattern A (Figure 35). The XRPD characterisation of the 5-MeO-DMT benzoate solids isolated to date from the single solvent mediated crystallisation of 5-MeO-DMT benzoate are concordant with Pattern A. This implies that there is no form or version modification 5-MeO-DMT benzoate under the conditions investigated. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate as described above.
Reverse addition anti-solvent driven crystallisation of 5-MeO-DMT benzoate
The first anti-solvent-driven crystallisation of 5-MeO-DMT benzoate, revealed a selection of suitable solvent/anti- solvent mixtures. Utilising relatively gradual anti-solvent addition and cooling from elevated temperature afforded only solids classed as Pattern A by XRPD. The suitable solvent/anti-solvent mixtures were re-examined with reverse addition of hot stock solution to cold anti-solvent to potentially rapidly precipitate a new and/or meta-stable solid form version of 5-MeO-DMT benzoate.
5-MeO-DMT benzoate, 165±0.5mg, was charged to vials A to F and dissolved in the minimal amount of solvent at 50°C as detailed in the Table below. Anti-solvent, 1ml, was charged to crystallisation tubes then cooled to -10°C and agitated at 400rpm. Aliquots of the stock solutions of 5-MeO-DMT benzoate, ca. 50mg, were charged directly to the anti-solvents. All crystallisation tubes afforded suspensions within 5 minutes of addition of the 5-MeO-DMT benzoate solution. Suspensions were isolated immediately in vacuo via isolute then transferred to vacuum oven and dried at 50°C for 18 hours.
Table - Summary of solvents, anti-solvents and observations
XRPD examination of most isolated solids (except for Al and Bl) were concordant with Pattern A (see Figures 36 and 37). XRPD examination of solids Al and Bl were concordant with one another but not Pattern A (Figures 38, 39). Lots Al and Bl shared diffractions with 5-MeO-DMT benzoate lot QI (a pattern previously identified as Form B). However, on closer inspection, QI was observed to share diffractions with Pattern A. As lot QI shared diffractions with both lots Al and Bl and Pattern A. The diffraction patterns for lots Al and Bl were considered to be characteristic of Pattern B.
The DSC thermograph of sample Al (Figure 41) revealed an endothermic event with onset ca. 110°C and major peak at 113.98°C, followed by an exotherm with onset 114.72°C and peak at 116.42°C, followed by a second endotherm with an onset of 123.00°C and peak at 123.72°C. DSC examination of sample Bl (Figure 42 and Figure 43) revealed a similar DSC thermograph to Al but the first endothermic event was larger, 108 J.g 1 compared 90 J.g 1 and only contained 2 peak temperatures of 109.00 and 110.32°C instead of the 3 present in Al. The exothermic event that immediately followed was smaller, 17 J.g 1 compared to 41 J.g -1. The second main endotherm was also smaller for Bl at 38 J.g 1 compared to 80 J.g 1 for Al. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate as described above. In an embodiment, there is provided crystalline 5-MeO-DMT salt, characterised by an endothermic or exothermic event in a DSC thermograph as substantially illustrated in any one of the Figures. In an embodiment, there is provided a composition comprising 5-MeO-DMT benzoate Pattern A form. In an embodiment, there is provided a composition comprising 5-MeO-DMT benzoate Pattern B form. In an embodiment, there is provided a composition comprising a mixture of 5-MeO-DMT benzoate Pattern A form and Pattern B form.
Example 22: Generation of the amorphous 5-MeO-DMT benzoate
Rapid in vacuo concentration
5-MeO-DMT benzoate, 101.55mg, was dissolved in THF, 4mL and clarified into a lOOmL round bottom flask. The solution was concentrated in vacuo 40°C at 200rpm. The liquid evaporated from the flask, yielding a concentrated clear colourless liquid residue around the flask. The residue was dissolved in acetone, 4ml, concentrated in vacuo at 40°C at 200rpm. The liquid evaporated from the flask, yielding a concentrated clear colourless liquid residue around the flask. Small crystals were visible on the inside of the flask, these were isolated after 18 hours affording 21-01- 051 A. Quench of melt
5-MeO-DMT benzoate was held at 125°C for 5 minutes by TGA then cooled to ambient over 3 minutes affording 21- 01-051 B. The sample was analysed immediately and after 20 hours held in a sealed container.
Lyophilisation
5-MeO-DMT benzoate, 200mg, was dissolved in deionised water, 10ml, and clarified through a 0.45pm nylon filter into a 500mL round bottom flask, then frozen into a thin layer. The flask was transferred to a vacuum and equilibrated to ambient temperature affording a fluffy white solid, 21-01-051 C. The solid transformed into gum over ca. 1 hour. The sample was analysed immediately and after 20 hours held in a sealed container.
Lyophilisation for amorphous solid equilibration
Lyophilisation was repeated as described above with 5-MeO-DMT benzoate, 800mg, dissolved in 25ml, affording 21- 01-051 D. The solid was heated to 60°C for 10 minutes then cooled yielding 21-01-051 E. The sample was analysed immediately. Figure 44 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E, E Particle size reduced and Pattern A reference. Figure 45 shows XRPD of 5-MeO-DMT benzoate lot 21-01-051 B, obtained from quenching the melt. Figure 46 shows XRPD of 5-MeO-DMT benzoate lot 21-01-051 C, obtained by lyophilisation. The XRPD patterns of 5-MeO-DMT benzoate 21-01-051 B and C were concordant with Pattern A, indicating that the amorphous form converts to Pattern A form in a sealed container at ambient temperature and pressure. The XRPD pattern of 5- MeO-DMT benzoate 21-01-051 A, the solid isolated by acetone concentration, was concordant with Pattern A form. Rapid in vacuo concentration did not produce the amorphous version. The XRPD patterns revealed 5-MeO-DMT benzoate 21-01-051 B and C to have an amorphous 'halo', indicating quenching molten material and lyophilisation produced amorphous 5-MeO-DMT benzoate. Figure 47 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01- 051 B after 20 hours, C after 20 hours, and Pattern A reference. The XRPD pattern of 5-MeO-DMT benzoate 21-01- 051 E were concordant with Pattern A, indicating that the amorphous form converts to Pattern A form at 60°C for 10 minutes. Figure 48 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E, E particle size reduced, and Pattern A reference.
DSC examination revealed amorphous 5-MeO-DMT benzoate 21-01-051 C and D obtained by lyophilisation, contained an exothermic event with a peak temperature between 65.63 and 70.84°C, followed by a broad endothermic shoulder leading into a endothermic event with a peak temperature between 120.20 and 121.22°C. The major endothermic event is ca. 3°C lower compared to Pattern A form material. Figure 49 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 A, C, and D at lO’C.min-1, isolated from acetone concentrate, 051 A, and lyophilisation, 051 C and 051 D. DSC examination revealed 5-MeO-DMT benzoate 21-01- 051 C post 20 hours no longer contained an exothermic event and the endothermic event at ca. 123°C was sharper and concordant with Pattern A form. Figure 50 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 C and C post 20 hours at 10°C.min -1. Amorphous 5-MeO-DMT benzoate can be generated by lyophilisation of an aqueous solution and the quenched melt. The amorphous 5-MeO-DMT benzoate will convert to Pattern A form material on standing. In one embodiment, there is provided an amorphous 5-MeO-DMT benzoate. In one embodiment, there is provided a composition comprising an amorphous 5-MeO-DMT benzoate. In one embodiment, there is provided a composition comprising an amorphous 5-MeO-DMT benzoate salt produced as detailed above or below.
Example 23: Further characterisation of amorphous 5-MeO-DMT benzoate
The thermal examination of amorphous 5-MeO-DMT benzoate by DSC and hot stage microscopy revealed a crystallisation event and endothermic melt. The endothermic melt is not consistent with the DSC thermograph of Pattern A form.
The solvent mediated equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation afforded Pattern A by XRPD and DSC from all solvents except anisole. New variations were generated. Amorphous 5-MeO-DMT benzoate generated by lyophilisation, 21-01-051 D (21-01-051) was examined by hot-stage microscopy at a heating rate of 5°C.min-l for corroboration with the DSC thermograph of the amorphous solid.
Initially, 5-MeO-DMT benzoate was a sticky translucent gum (Figure 52) that upon heating to 54.21°C reduced in viscosity and spread out into a thinner uniform layer (Figure 53). At 54.21°C the liquid began to crystallise (Figure 53) which neared completion by 74.21°C (Figure 54). The newly formed crystals began to melt at 114.24°C (Figure 55) which neared completion by 120.14°C (Figure 56). The hot stage microscopy examination corroborated with events in the DSC thermograph (Figure 51); the crystallisation exotherm at ca. 65°C and the melt endotherm at ca. 115°C.
Figure 51 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-051 D, large scale lyophilised material, with temperature stamps corresponding to hot-stage microscopy images. Figure 52 shows Micrograph image of 5-MeO- DMT benzoate lot 21-01-051 D at 30.02°C. Figure 53 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01- 051 D at 54.21°C. Figure 54 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 74.21°C. Figure 55 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 114.23°C. Figure 56 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 120.14°C.
Solvent mediated equilibration of amorphous 5-MeO-DMT benzoate with thermal manipulation
The action of agitating the amorphous version of a solid in a series of solvents can lead to dissolution and crystallisation to more ordered and energetically stable solids. In this manner, alternate crystal forms of a solid can be potentially generated for comparison and evaluation. Amorphous 5-MeO-DMT benzoate 21-01-51 D, 24x 25 ±2mg was transferred to crystallisation tubes and solvent, 0.125mL charged as detailed in the Table below. The mixtures were agitated at 300rpm at 25°C for 30 minutes. Solvent, 0.125mL, was charged to relevant mixtures and equilibrated for 18 hours. Mixtures were heated to 55°C for 8 hours then cooled to 25°C over 1 hour then equilibrated for 18 hours at 300rpm, observations following each manipulation is detailed in the Table below. Suspensions were transferred to Isolute tubes for isolation and dried under vacuum for 2 mins then dried in vacuo at 50°C for 24 hours. XRPD examination of the solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation revealed all powder patterns to be concordant with Pattern A (Figure 57 and Figure 58).
Figure 57 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation. Figure 58 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 M isolated from the equilibration of amorphous 5-MeO-DMT benzoate in a,a,a-trifluorotoluene with thermal modulation with lot 20-37-64 (Pattern A). The DSC examination of a selection of 5-MeO-DMT benzoate solids classified as Pattern A revealed a major endothermic event with onset temperatures between 121.88 and 123.39°C and peak temperatures between 123.66 and 124.11°C. This endotherm is characteristic of Pattern A form (Figure 59). 5-MeO-DMT benzoate 21-01-054 Q, solid isolated from anisole, contained events within the major endothermic event with peak temperatures of 111.64°C and 116.92°C (Figure 60, Figure 61). This is in line with the DSC thermograph of 5-MeO-DMT benzoate isolated following equilibration in anisole, 20-37-64-R1, although less pronounced.
Figure 59 shows DSC thermograph comparison of a selection of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A form. Figure 60 shows DSC thermograph expansion comparison of a selection of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A form, highlighting an event in lot 21-01-054 Q, solid isolated from anisole. Figure 61 shows Expanded DSC thermograph expansion highlighting an event in lot 21-01-054 Q, isolated from anisole.
Example 24: Pattern C
Additional 5-MeO-DMT benzoate Pattern B form material was required for further characterisation. The procedure of charging 5-MeO-DMT benzoate/IPA solution to cold toluene was employed. 5-MeO-DMT benzoate 20/20/150FP2, 250mg, was dissolved in IPA, 5ml, and heated to 50°C and clarified. The clarified solution, 2x 2ml, lOOmg of 5-MeO- DMT benzoate, was charged to toluene, 4ml, at -10°C and agitated at 750rpm. Upon addition, both mixtures remained as clear colourless solutions. After 30 minutes a solid had formed in tube A. The solid, 21-01-060 A, was isolated immediately via isolute and dried in vacuo for 2 minutes. A portion, 21-01-060 Al was removed for XRPD analysis, a portion was dried in vacuo at 50°C for 20 hours, 21-01-060 A2.
After 50 minutes a solid had formed in tube B and was allowed to equilibrate at -10°C and agitated at 750rpm for 3 hours. The solid, 21-01-060 B, was isolated immediately via isolute and dried in vacuo for 2 minutes. A portion 21- 01-060 Bl was removed for XRPD analysis, the remainder was dried in vacuo at 50°C for 20 hours, 21-01-060 B2.
Samples 21-01-060 Al and 21-01-060 Bl were air dried under ambient conditions for 20 hours and assessed by XRPD and DSC. Immediately following isolation, 21-01-060 Al was analysed by XRPD. This revealed a new diffraction pattern that was not concordant with Pattern A or Pattern B. This is referred to as Pattern C. The XRPD pattern of 21-01-060 Al (2 mins air dried) was reacquired following a further 1 hour of air drying under ambient conditions (Figure 62). Additional diffractions were present in the XRPD of 21-01-060 Al (air dried 1 hour) compared to 21-01- 060 Al (2 mins air dried), which suggests conversion to Pattern B form (Figure 63).
Figure 62 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 2 minutes, lot 21-01- 049 Bl, Pattern B, and lot 20-37-64, Pattern A. Figure 63 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 1 hour and lot 21-01-060 Al-air dried 2 minutes. Figure 64 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 2 minutes, lot 21-01-060 Al-air dried 1 hour, and lot 21-01-049 Bl, Pattern B. The DSC thermograph of 5-MeO-DMT benzoate 21-01-060 Al (air dried 1 hour) (Figure 65 and Figure 66) revealed a minor broad endotherm with a peak temperature of 108°C which is considered characteristic of Pattern C form solid.
This is followed by an exotherm with a peak temperature of 112.35°C which is considered to be the conversion of Pattern C form to Pattern A form, since the main endotherm has a peak temperature of 124.12°C, which is characteristic of Pattern A form. Figure 65 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour. Figure 66 shows DSC thermograph expansion of 5- MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour. An XRPD pattern of 5-MeO-DMT benzoate lot 21-01-060 Al was acquired following a total of 20 hours air drying. This revealed the pattern (Figure 67) to be concordant with SPS552021-01-049 Bl, Pattern B, but contained diffractions indicative of Pattern C such as 10.3° 20 (Figure 67). Figure 67 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 20 hours, lot 21-01-060 Al air dried 2 minutes, and lot 21-01-049 Bl, Pattern B ref.
5-MeO-DMT benzoate 21-01-060 Bl produced from reverse anti-solvent addition, equilibrated for 3 hours, then isolated and air drying at ambient temperature. Immediately following isolation, the solid was analysed by XRPD. This revealed a diffraction pattern concordant with 21-01-060 Al, Pattern C (Figure 68). The XRPD pattern (Figure 69) was reacquired following 20 hours air drying and revealed the solid was still Pattern C but contained diffractions at 17.2° and 19.5 20 indicative of Pattern B. Figure 68 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 2 mins and Al isolated immediately then air dried for 2 minutes. Figure 69 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 20 hours and Bl isolated after 3 hours equilibration then air dried for 2 minutes, and lot 21-01-049 Bl, Pattern B.
Example 25: Investi ation of the impact of solvent vapour diffusion upon amorphous 5-MeO-DMT benzoate
Subjecting an amorphous solid to solvent vapour is considered to be a low energy process for inducing form or version change of the solid in order to generate meta stable versions and/or solvates from the amorphous solid for comparison and evaluation. 5-MeO-DMT benzoate, 497.44mg, was dissolved in deionised water, lOmL, and clarified into a 500mL round bottom flask and lyophilised as detailed previously. The fluffy white solid produced, 12x 25mg, was charged to HPLC vials and placed in a sealed container with ca. 2mL of solvent. The solvents employed and observations are detailed in the Table below. Following equilibration for 7 days, solids were transferred to XRPD sample holder directly and analysed by XRPD. DSC was collected for all notable samples by XRPD and a selection of Pattern A form solids.
XRPD pattern for all samples (Figure 70) except for 21-01-058 D and 21-01-058 G, isolated from anisole and toluene respectively, were concordant with Pattern A form material (Figure 71). Figure 70 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 solids isolated from amorphous 5-MeO-DMT benzoate exposed to solvent vapour. Figure 71 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 K, isolated from amorphous 5-MeO-DMT benzoate exposed to solvent vapour, with lot 20-37-64, Pattern A. The DSC thermograph comparison of a selection of Pattern A form solids (Figure 72) revealed an endothermic event with peak temperatures between 123.69°C and 124.14°C which is indicative of Pattern A form and corroborates the XRPD data. The DSC thermograph of lot 21-01-058 G (not Pattern A form, by XRPD) demonstrates a minor endothermic event prior to the main endotherm and is elaborated on below. Figure 72 shows DSC thermograph comparison of 5-MeO- DMT benzoate lot 21-01-058 B, lot 21-01-058 F, lot 21-01-058 K, and lot 21-01-062 G.
Example 26: Pattern D
5-MeO-DMT benzoate 21-01-058 D, solid isolated from exposure of amorphous 5-MeO-DMT benzoate to anisole vapour for 7 days
XRPD of 5-MeO-DMT benzoate lot 21-01-058 D, isolated from amorphous 5-MeO-DMT benzoate exposed to anisole vapour, revealed a unique powder pattern (Figure 73 and Figure 74). The diffractions of 21-01-058 D are similar to Pattern C but vary in intensity and position (Figure 75). Figure 73 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 20-37-64, Pattern A, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours). Figure 74 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours). Figure 75 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours). The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-058 D (Figure 76), isolated from amorphous 5-MeO-DMT benzoate exposed to anisole vapour revealed an endothermic event with a peak temperature of 118.58°C. This corroborates the XRPD data, confirming a new version has been isolated.
Figure 76 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-058 D, isolated from exposure of anisole vapour to amorphous form. Amorphous 5-MeO-DMT benzoate exposed to anisole vapour afforded an anisole hemisolvate, nominated herein as Pattern D form. The XRPD pattern of Pattern D form is similar to Pattern C, the toluene hemi-solvate, but with variance in peak position. Amorphous 5-MeO-DMT benzoate exposed to toluene vapour afforded a mixed form version that was predominantly Pattern A form with some evidence of Pattern C form, the toluene hemi-solvate, observed by XRPD and DSC. Amorphous 5-MeO-DMT benzoate exposed to all other solvent vapours returned exclusively Pattern A by XRPD and DSC.
Example 27: Pattern E
5-MeO-DMT benzoate Pattern C form was isolated via reverse anti-solvent addition of isopropanol solution of 5- MeO-DMT benzoate to toluene, this solid is believed to be a hemi-solvate which when desolvated afforded Pattern B form. Pattern B form has been accessed by equilibration of 5-MeO-DMT benzoate in anisole and chlorobenzene. Pattern B form may be accessed from anisole and chlorobenzene hemi-solvates, consequently reverse anti-solvent addition to chlorobenzene and anisole is believed to afford a hemi-solvate as with toluene.
5-MeO-DMT benzoate 20/20/150FP2, 650mg, was charged to sample vial with IPA, 13ml, and heated to 50°C. The clear solution was clarified through a 0.45pm nylon syringe filter. Anti-solvent, 4ml, was charged to crystallisation tubes and cooled to -10°C with agitation via stirrer bead at 750rpm as detailed in the Table below. IPA stock solution at 50°C, 2ml, was charged to cold anti-solvent, 4ml, at -10°C. Observations are detailed in the Table below, with B, D, and F isolated immediately. Tubes A, C, and E were equilibrated for 3 hours then isolated. Suspensions were transferred to isolute cartridge and dried in vacuo for NMT 60 seconds and analysed immediately, following 4 hours, and 44 hours open to atmosphere. 5-MeO-DMT benzoate 21-01-064 E was damp after air drying for 60 seconds.
5-MeO-DMT benzoate 21-01-064 D was isolated immediately following the formation of the suspension afforded by the addition of concentrated IPA solution to chlorobenzene at -10°C. The XRPD revealed the diffraction pattern of 5-MeO-DMT benzoate lot 21-01-064 D was similar to 21-01-060 Bl (air dried 2 minutes), Pattern C (Figure 77). Several diffractions including 19 and 20° 20 are slightly higher and lower compared to Pattern C which are not consequences of the sample presentation (Figure 78).
5-MeO-DMT benzoate lot 21-01-064 D is a new diffraction pattern, and defined herein as Pattern E. Figure 77 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes). Figure 78 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes). The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 D revealed a major bimodal endothermic event with peak temperatures of 110.31°C and 113.13°C (Figure 79), followed by a minor endothermic event with a peak temperature of 119.09°C. Figure 79 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 D at 10°C.min-l.
The 1H NMR spectrum of 5-MeO-DMT benzoate lot 21-01-064 D isolated immediately following equilibration revealed the stoichiometry of the salt to be 1:1 and also revealed a salt to solvent ratio for chlorobenzene of 1:0.512 and a salt to solvent ratio for IPA of 1:0.013. The isolated salt is a chlorobenzene hemi-solvate. There is no evidence of a Pattern A form endothermic at ca. 123°C in the DSC thermograph, 21-01-064 D (Figure 79) since it is considered that the residual chlorobenzene is inhibiting crystallisation of 5-MeO-DMT benzoate. 5-MeO-DMT benzoate 21-01- 064 C was isolated following a 3 hour equilibration of the suspension afforded by the addition of concentrated IPA solution to chlorobenzene at -10°C.
The XRPD revealed the diffraction pattern of 5-MeO-DMT benzoate lot 21-01-064 C was concordant with 21-01-064 D, Pattern E (Figure 80). Figure 80 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D. Figure 81 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D. The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 C revealed a major endothermic event with peak temperatures of 111.39°C, 113.22°C, andll4.35°C (Figure 82). The DSC thermograph of 21-01-064 C is similar to that of the thermograph of 21-01-064 D. Figure 82 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 C at 10°C.min-l. The 1H NMR spectrum of 5-MeO-DMT benzoate lot 21-01-064 C isolated following a 3 hour equilibration revealed the stoichiometry of the salt to be 1:1 and also revealed a salt to solvent ratio for chlorobenzene of 1:0.506 and a salt to solvent ratio for IPA of 1:0.004. The isolated salt is a chlorobenzene hemi- solvate. The XRPD of 5-MeO-DMT benzoate lot 21-01-064 C (4 hours air dried) revealed a diffraction pattern concordant with 21-01-064 C, Pattern E. The XRPD of 5-MeO-DMT benzoate lot 21-01-064 C (44 hours air dried) revealed a diffraction pattern concordant with 21-01-064 C and 21-01-064 C (4 hours air dried), Pattern E. The XRPD of 5-MeO-DMT benzoate lot 21-01-064 F revealed a diffraction pattern concordant with 21-01-058 D, Pattern D from the vapour diffusion investigation of amorphous 5-MeO-DMT benzoate in anisole, but more crystalline and does not contain minor diffractions characteristic of Pattern A. The XRPD of 5-MeO-DMT benzoate 21-01-064 E revealed a diffraction pattern concordant with 21-01-064 F, Pattern D.
The XRPD of 5-MeO-DMT benzoate 21-01-064 E (air dried 4 hours) revealed a diffraction pattern concordant with 21-01-064 E, Pattern D. The XRPD of 5-MeO-DMT benzoate 21-01-064 E (air dried 44 hours) revealed a diffraction pattern concordant with 21-01-064 E, Pattern D but with an additional diffraction at 18.3° 20, which is believed to be an indication of Pattern B.
Example 28: Further discussion of patterns B io E
Pattern B
Below is a Table which summarises lots of 5-MeO-DMT benzoate with predominantly Pattern B form compositional and crystallographic characteristics.
Below is a Table which summarises predominantly Pattern B thermal characteristics.
5-MeO-DMT benzoate lot 21-01-049 Bl was produced via reverse anti-solvent addition of an IPA solution to toluene, isolated immediately, then dried in vacuo at 50°C. XRPD revealed a diffraction pattern that was defined as Pattern
B. DSC examination identified an endothermic event at 110°C which coincides with the boiling point of toluene, this is followed by an endothermic event immediately followed by an exothermic event indicating the melt-crystallisation of Pattern B form to Pattern A form then the endothermic event indicating the melt of Pattern A form material. 1H NMR revealed low amounts of residual toluene and no IPA.
5-MeO-DMT benzoate lot 21-01-060 A2 was produced by the same methodology as 049 Bl except on a larger scale and afforded an identical product by XRPD and DSC but contained residual IPA by 1H NMR.
5-MeO-DMT benzoate lot 21-01-049 Al was produced by the same methodology as 049 Bl except it was initially dissolved in methanol, XRPD revealed a powder pattern concordant with Pattern B with some Pattern C. 1H NMR revealed a salt to toluene ratio of 1:0.03. DSC examination revealed a similar thermograph to 049 Bl but the first endothermic event at 110°C was larger and the subsequent endothermic melt of Pattern B form is bimodal and peaks at a lower temperature. Following the melt of Pattern B form, Pattern A form crystallises, and melts as expected. 5-MeO-DMT benzoate lot 21-01-060 B2 was produced by the same methodology as 060 A2 but equilibrated for 3 hours before isolation and drying in vacuo. XRPD revealed a mixture of Pattern B with some Pattern
C. 1H NMR revealed a salt to toluene ratio of 1:0.05. DSC examination revealed a similar thermograph to 049 Al (a mixture of Pattern B and C forms) but the Pattern B form melt endothermic event is not bimodal. The endothermic event at 110°C is considered to be a consequence of a slightly increased amount of toluene in the sample in the form of the toluene hemi-solvate.
5-MeO-DMT benzoate lot 21-01-060 Al (air dried 20 hours) was produced by the same methodology as 060 A2 but was air dried instead of at 50°C in vacuo. XRPD revealed a mixture of Pattern B and C. 1H NMR revealed a salt to toluene ratio of 1:0.04. However, 060 Al contained a significant amount more IPA than other samples (1:0.2 instead of 1:0.05). This may have modified the endothermic events during the DSC examination of the sample, but the Pattern A form melt endothermic event is present. 5-MeO-DMT benzoate lot 21-01-047 J was produced by crystallisation from chlorobenzene at 50°C and dried in vacuo at 50°C. XRPD revealed the sample to be a mixture of Pattern B and some Pattern A. DSC examination revealed an endothermic event similar to the endothermic event considered to be loss of toluene, which is believed to indicate the loss of chlorobenzene. The melting endotherm of Pattern B form occurs earlier than for 049 Bl but the crystallisation of Pattern A form is very exothermic and is accompanied by a melt of Pattern A form.
5-MeO-DMT benzoate Pattern B form material contains a characteristic endo-exothermic event as it melts then crystallises as Pattern A form, Pattern B form is produced by the desolvation of hemi-solvates, therefore an endothermic event characteristic of the residual hemi-solvate is present in all samples isolated. For those solids that contain toluene at low levels, which is believed to be the hemi-solvate version of the salt, the thermal characteristics will be modified by the loss of toluene.
Pattern C
Below is a Table which summarises lots of 5-MeO-DMT benzoate with predominantly Pattern C compositional and crystallographic characteristics.
Below is a Table which summarises predominantly Pattern C form thermal characteristics.
5-MeO-DMT benzoate lot 21-01-064 B was produced by reverse anti-solvent addition of an IPA solution to toluene. XRPD revealed Pattern C which was supported by a ratio of 1:0.5 of salt to toluene by 1H NMR indicating a toluene hemi-solvate. DSC examination revealed a bimodal endothermic event with peak temperatures of 111.3°C and 112.1°C, this indicates the endothermic event at 111°C in the Pattern B mixtures was a result of residual Pattern C. There were endothermic events indicative of Pattern B form, which suggested transformation to Pattern B form then Pattern A form. 5-MeO-DMT benzoate lot 21-01-064 A was produced by the same methodology as 064 B but was equilibrated for 3 hours before isolation. XRPD and 1H NMR revealed identical characteristics as 064 B. However, DSC examination revealed a different major multi-modal endothermic event with a peak temperature of 115.0°C.
5-MeO-DMT benzoate lot 21-01-064 A (air dried 44 hours) and 21-01-060 Bl air dried (20 hours) were produced similarly to 064 A but air dried for longer. XRPD revealed a mixture of Pattern C and Pattern B for both, 1H NMR revealed less toluene in 060 Bl than for 064 A, which is believed to be a result of air drying which supports the presence of Pattern B form in the sample by XRPD. DSC examination revealed an endothermic event with a peak temperature of 111.3°C for both, followed by multiple unique endothermic events. 5-MeO-DMT benzoate lot 21-01- 064 A (air dried 4 hours) was produced by air drying 064 A. XRPD revealed a mixture of Pattern C with some Pattern B. DSC examination revealed a broad exothermic event between 105 and 113°C followed by a weak endothermic event indicative of Pattern C form and endothermic events indicative of Pattern B form. The change to the heating rate is the cause of the change to thermal behaviour, as the DSC thermograph of 21-01-064 A (44 hour air dried) sample is similar to 21-01-064 A the transformation of Pattern C form occurred in situ during the examination.
5-MeO-DMT benzoate 21-01-060 Al (air dried 1 hour) was produced by the same methodology as 064 A but isolated immediately. XRPD revealed a mixture of Pattern C and some Pattern B. DSC examination revealed a thermograph indicative of Pattern B form with a minor exothermic event at ca 109°C. 5-MeO-DMT benzoate Pattern C form is a toluene hemi-solvate it has no characteristic endothermic event except for a melt between 110°C and 115°C. The XRPD pattern of the toluene hemi-solvate of 5-MeO-DMT benzoate is distinct to 5-MeO-DMT benzoate. Desolvation may occur under ambient conditions and it is considered that Pattern B form is produced. The thermal characteristics will be influenced by the loss of toluene during DSC examination.
Pattern D
The Table below is a summary of predominantly Pattern D form compositional and crystallographic characteristics.
The table below shows a summary of predominantly Pattern D form thermal characteristics. 5-MeO-DMT benzoate lot 21-01-064 F was produced by reverse anti-solvent addition of an IPA solution to anisole and isolated immediately. XRPD revealed a diffraction pattern concordant with Pattern D, which was supported by a ratio of 1:0.503 for anisole by 1H NMR indicating a hemi-solvate. DSC examination revealed a bimodal endothermic event with peak temperatures of 118.61°C and 119.21°C.
5-MeO-DMT benzoate lot 21-01-064 E was produced by reverse anti-solvent addition of an IPA solution to anisole, then equilibrated for 3 hours before isolation. XRPD revealed Pattern D but this was not supported by 1H NMR which revealed a ratio of salt to anisole of 1:1.04, the isolated solid was damp after isolation. DSC examination revealed very poorly defined broad endothermic events with peak temperatures of 113.51°C and 161.93°C, the endothermic event at 113.51°C is believed to be a result of the melting of the hemi-solvate present by XRPD followed by evaporation of anisole. The DSC thermograph is not considered representative of Pattern D form due to the solvent content. 5-MeO-DMT benzoate lot 21-01-058 D was produced by exposure of the amorphous form to anisole vapour. XRPD revealed a mixture of Pattern D and some Pattern A diffractions which was supported by 1H NMR which revealed a ratio of salt to anisole of 1:0.47 indicating an anisole hemi-solvate. DSC examination revealed an endothermic event with a peak temperature of 118.6°C, which is concordant with the data collected from 064 F. However, the melt of Pattern A form is not revealed in the DSC thermograph, this could be modified by the liberated anisole solvent present in the sample.
5-MeO-DMT benzoate lot 21-01-064 E (air dried 4 hours) was produced by air drying 064 E for 4 hours. XRPD revealed Pattern D. DSC examination was performed at 2.5°C.min-l with the aim to resolve the bimodal endothermic event observed in the thermograph of 064 E. DSC examination revealed a minor endothermic event with a peak temperature of 111.24°C, this endothermic event is concordant with the broad endothermic event observed in 064 E. The better resolution of this endothermic is believed to be a result of the slower heating rate, or due to removal of residual anisole by air drying. This was followed by a major endothermic event with a peak temperature of 117.90°C which is concordant with 058 D and 064 F. 5-MeO-DMT benzoate lot 21-01-064 E (air dried 44 hours) was produced by air drying 064 E (air dried 4 hours) for a further 40 hours. XRPD revealed a mixture of Pattern D with some Pattern B diffractions. DSC examination revealed a thermograph concordant with 064 E (4 hours air dried). The Pattern B form content was not evident in the DSC thermograph this is believed to be caused by the liberated anisole solvent present in the sample, similar to 058 D. 5-MeO-DMT benzoate Pattern D form is an anisole hemi- solvate and has been produced directly from exposure of the amorphous form to anisole vapour as well as reverse anti-solvent addition from an IPA solution to cold anisole. No characteristic thermal behaviour has been identified although, endothermic events near 118°C are common and the lack of recrystallisation to Pattern B or A forms is believed to be due to the presence of residual anisole.
Pattern E
The Table below is a summary of predominantly Pattern E form compositional and crystallographic characteristics. The table below is a summary of predominantly Pattern E form thermal characteristics, the endothermic event at 123.7°C is characteristic of Pattern A.
5-MeO-DMT benzoate lot 21-01-064 D was produced by reverse anti-solvent addition of an IPA solution to chlorobenzene. XRPD revealed Pattern E, this was supported by 1H N MR which revealed a ratio of salt to chlorobenzene of 1:0.506 indicating a chlorobenzene hemi-solvate. DSC examination revealed a bimodal endothermic event with peak temperatures of 111.3°C and 113.1°C, followed by a minor endothermic event with a peak temperature of 119.1°C. 5-MeO-DMT benzoate lot 21-01-064 C was produced by reverse anti-solvent addition of an IPA solution to cold chlorobenzene, then equilibrated for 3 hours before isolation. XRPD revealed Pattern E, this was supported by 1H NMR which revealed a ratio of salt to chlorobenzene of 1:0.512 indicating a hemi-solvate. DSC examination revealed a trimodal endothermic event with peak temperatures of 111.3°C, 113.1°C, and 114.3°C. There are similarities between DSC thermographs of 064 D and C but the endothermic event at 119.1°C is not present in 064 C and 064 D did not reveal a trimodal endothermic event. The differences in the DSC thermograph are of note since the XRPD patterns were identical and 1H NMR revealed hemi-solvates.
5-MeO-DMT benzoate lot 21-01-064 C (air dried 4 hours) was produced by air drying 064 C for 4 hours. XRPD revealed Pattern E. DSC examination was performed at 2.5°C.min 1 and revealed a broad exothermic event followed by a minor endothermic event at 114.3°C but much weaker in comparison to the same endothermic event in 064 C. This was followed by the major endothermic event at 123.7°C which is indicative of Pattern A form. The DSC thermograph is similar to the previous 2.5°C.min 1 DSC examination and is generating Pattern A form during the DSC examination. 5-MeO-DMT benzoate lot 21-01-064 C (air dried 44 hours) was produced by air drying 064 C (air dried 4 hours) for a further 40 hours. XPRD revealed Pattern E. DSC examination revealed a bimodal endothermic event with peak temperatures of 115.1°C and 115.8°C. The endothermic event of 064 C (air dried 44 hours) is similar to 064 C but peaks at a slightly higher temperature. 5-MeO-DMT benzoate Pattern E form is a chlorobenzene hemi-solvate with no defined thermal characteristics except for a multi-modal endothermic event between 110 and 117°C. Similarly, to the anisole hemi-solvate, Pattern A and B forms do not recrystallise from the melt. Chlorobenzene hemi-solvate appears to not desolvate when open to ambient conditions and did not desolvate over 44 hours.
Example 29: Hemi-solvates
Equilibration of suspensions in anti-solvent (toluene, anisole, and chlorobenzene) at -10°C afforded the expected hemi-solvate by XRPD and 1H NMR spectroscopy and TGA. The partial desolvation of hemi-solvates is considered to afford multi-modal endothermic events observed in the DSC thermographs, a consequence of changing composition and the applied heating rate. Desolvation of hemi-solvates in vacuo at 50°C for 22 hours afforded Pattern B form material by XRPD, DSC, however, some residual hemi-solvate remained in all samples. The DSC thermograph of the hemi-solvates were similar to those isolated from IPA/antisolvent but with minor differences which are considered to be a consequence of how they were prepared. Drying 5-MeO-DMT benzoate toluene hemi-solvate and chlorobenzene hemi-solvate in vacuo at 50°C for 67 hours afforded Pattern A form, but the anisole hemi-solvate afforded predominantly Pattern B form. Addition of 5-MeO-DMT benzoate/IPA solution to toluene at -10°C then air dried for 5 minutes afforded the toluene hemi-solvate when performed on a lg input. Drying 5-MeO-DMT benzoate toluene hemi-solvate at 50°C for 24 hours afforded Pattern B form. 5-MeO-DMT benzoate batches 20/53/057-FP and 20/20/123FP demonstrated similar particle habits of large hexagonal/rhombus plates (ca. 500pm to 1 mm in length) and some smaller plates that demonstrated accretion on the plate surfaces and significant evidence of broken fine particles and plates, potentially due to attrition. This was different to batches 20/20/150FP2 T=0 and 20/20/154FP which demonstrated similar particle habits of accreted, jagged clusters of irregular plates, (ca. 250 to 600pm in length) and broken, irregular plates and crystallites (some <20pm in length) that were indicative of particle attrition. The significant difference in particle size and habit between the batches is believed to have an impact on isolation, flowability and kinetic dissolution rate of the solids, highlighting the importance of a controlled crystallisation.
Example 30: Patterns F and G
5-MeO-DMT benzoate methyl benzoate hemi-solvate (Pattern F form) has been isolated from controlled cooling of a clarified 5-MeO-DMT benzoate methyl benzoate solution from 50°C to -10°C. 5-MeO-DMT benzoate 2- chlorotoluene hemi-solvate (Pattern G form) has been isolated from controlled cooling of a clarified 5-MeO-DMT benzoate 2-chlorotoluene solution from 80°C to -10°C. Equilibration in a,a,a-trifluorotoluene did not afford a hemi- solvate as anticipated from a monosubstituted aromatic solvent. Equilibration in cumene afforded Pattern B form, which indicated a cumene hemi-solvate. DVS examination of amorphous 5-MeO-DMT benzoate revealed a weight loss of ca. 2% indicating the elimination of a component and confirming that a stable hydrate of 5-MeO-DMT benzoate was not isolated. Pattern A form is the most stable version of 5-MeO-DMT benzoate and is the thermodynamically favoured product except when isolated from a small selection of solvents, which afforded the respective hemi-solvate. Stability studies revealed conversion of all patterns to Pattern A form when dried in vacuo at 50°C. However, Pattern B form has been shown to be stable when open to atmosphere at ca. 20°C for up to 12 days. Pattern C form underwent partial conversion to Pattern B form within 24 hours when open to atmosphere at ca. 20°C, but failed to convert any further from a Pattern B/C mixed version over an additional 11 days. FTIR spectra for Patterns A, B and C were overall similar though there were some unique bands in Pattern A form and absent bands that were otherwise present and shared by Patterns B and C forms. Controlled cooling crystallisation investigation with an expanded solvent selection
Initial cooling crystallisation investigation of 5-MeO-DMT benzoate revealed Pattern A form was isolated from most solvents except chlorobenzene which was consistent with Pattern B form. The range of solvents was expanded, with an emphasis on esters and aromatics.
5-MeO-DMT benzoate lot 20/20/150FP2, 50mg ±lmg, was charged to crystallisation tubes A-L. Minimal solvent at 50°C was charged to afford a clear solution as detailed in the Table below. Crystallisation tubes I, J, K, and L remained as suspensions at 12.5mg.ml-l at 50°C and so were heated to 80°C to afford clear solutions. Solutions were clarified into crystallisation tubes at 50°C and were cooled to -10°C at a rate of 10°C.hr-l, then equilibrated at -10°C for 12 hours, then agitated at -10°C at 400rpm for 30 minutes which afforded a mobile suspension for all samples except Sample I which remained a solution. Further equilibration with agitation at -10°C at 400rpm for 3 hours afforded a thin suspension. All samples were isolated via isolute cartridge and air dried for 5 minutes before characterisation.
Sample F isolated from methyl benzoate was a thick white paste after air drying for 5 minutes and was left to air dry on the XRPD sample holder for a further 30 minutes which then afforded a dry powder.
5-MeO-DMT benzoate lots 21-01-073 B, C, D, E, G, H, and L were isolated from n-propyl acetate, isopropyl acetate, iso-butyl acetate, ethyl formate, methyl propionate, 4-methyl-2-pentanone, and a,a,a-trifluorotoluene respectively. The XRPD of these samples revealed powder patterns concordant with 5-MeO-DMT benzoate lot 20-37-64, Pattern A. The DSC thermograph of a selection of pattern A material revealed a common endothermic event with a peak temperature ranging from 123.07°C to 124.17°C with an enthalpy of ca. 140 J.g-1, which is characteristic of Pattern A form. The 1H NMR spectra of 5-MeO-DMT benzoate lots 21-01-073 B, E, H, and L isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio ranging from 1:0.0155 to 1:0.027. 5-MeO-DMT benzoate lot 21-01-073 A was isolated from controlled cooling of a methyl acetate solution from 50°C to -10°C, then air dried for 5 minutes.
The XRPD of 5-MeO-DMT benzoate lot 21-01-073 A revealed the diffraction pattern was concordant with 5-MeO- DMT benzoate lot 20-37-64, Pattern A (Figure 83), but featured diffractions at 21 and 24.6 °20 that were more intense. The difference in intensity was likely a result of preferred orientation.
Figure 83 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 A, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A. The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 A revealed an endothermic event with a peak temperature of 123.58°C, this is characteristic of Pattern A form. The 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 A isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of methyl acetate of 1:0.033. 5-MeO- DMT benzoate lot 21-01-073 F was isolated from controlled cooling of a methyl benzoate solution from 50°C to - 10°C, then air dried for 5 minutes. After air drying for 5 minutes the sample was a paste, air drying further for 30 minutes afforded a damp powder. The XRPD of 5-MeO-DMT benzoate lot 21-01-073 F revealed an XRPD pattern with an amorphous halo (Figure 84). The sample was re-run after further air drying. The XRPD of 5-MeO-DMT benzoate 21-01-073 F (re-run) revealed a diffraction pattern concordant with the initial measurement but with a reduced amorphous halo (Figure 85). The diffraction pattern demonstrated some similarities with both Pattern A and B (Figure 86) but the presence of unique diffractions and absence of characteristic Pattern A and Pattern B diffractions indicate this material to be a unique solid form version, identified herein as Pattern F form.
Figure 84 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F and 21-01-073 F rerun. Figure 85 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A. Figure 86 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A. The DSC thermograph of 5-MeO-DMT benzoate lot 21-01- 073 F (re-run) revealed a broad endothermic event with a peak temperature of 90.50°C, this was followed by a small endothermic event with a peak temperature of 106.65°C. This was followed by a broad and shallow endothermic event with a peak temperature of 180.35°C. DSC examination was repeated after the sample was stored in a sealed container for 24 hours. The DSC thermograph revealed a major endothermic event with a peak temperature of 95.33°C, followed by an exothermic event with a peak temperature of 102.70°C. This was followed by an endothermic event with a peak temperature of 113.77°C.
The 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 F isolated following controlled cooling, then air dried for 5 minutes, revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of 1:0.59. After air drying, the paste-like consistency indicated the presence of methyl benzoate, the visually damp powder following 30 minutes of air drying, indicates that residual methyl benzoate was still present. However, due to the unique diffraction pattern and DSC thermograph, combined with the stoichiometry close to 1:0.5 and the propensity of the 5-MeO-DMT benzoate salt to form hemi-solvates with aromatic solvents, this sample is believed to be a methyl benzoate hemi-solvate.
5-MeO-DMT benzoate lot 21-01-073 I was isolated from controlled cooling of a 5-MeO-DMT benzoate cumene solution from 50°C to -10°C, then air dried for 5 minutes. The XRPD of 5-MeO-DMT benzoate lot 21-01-073 I revealed the diffraction pattern was concordant with SPS552021-01-049 Bl, Pattern B. The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 I revealed an endothermic event with a peak temperature of 109.24°C with a broad shoulder at ca. 100°C. This was followed by an exothermic event with a peak temperature of 111.35°C, then an endothermic event with a peak temperature of 120.31°C. This was followed by a broad exothermic event with a peak temperature of 146.19°C. This thermal profile resemble historic Pattern B samples, although the post-final melt exotherm was known.
The 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 I isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of 1:0.035. 5- MeO-DMT benzoate lot 21-01-073 J was isolated from controlled cooling of an 5-MeO-DMT benzoate toluene solution from 50°C to -10°C, then air dried for 5 minutes. The XRPD of 5-MeO-DMT benzoate lot 21-01-073 J revealed the diffraction pattern was concordant with 5-MeO-DMT benzoate lot 21-01-064 A, Pattern C. The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 J revealed an endothermic event with peak temperatures of 110.00°C, 115.03°C, and 120.60°C. The DSC thermograph is similar to 5-MeO-DMT benzoate lot 21-01-071 Cl, previously isolated Pattern C form material, although the minor peaks are different which is believed to be a consequence of sample preparation. The 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 J isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of 1:0.473, confirming the isolation of the Pattern C form toluene hemi-solvate.
5-MeO-DMT benzoate lot 21-01-073 K was isolated from controlled cooling of an 5-MeO-DMT benzoate 2- chlorotoluene solution from 50°C to -10°C, then air dried for 5 minutes. The XRPD of 5-MeO-DMT benzoate lot 21- 01-073 K revealed a diffraction pattern that was unique (Figure 87) and is herein identified as Pattern G.
Figure 87 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 K, 21-01-049 Bl, Pattern B, and 20-37-64.
The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 K revealed an endothermic event with peak temperatures of 111.28°C and 119.61°C.
The 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 K isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of 1:0.516, thus Pattern G form is believed to correspond to a 2-Chlorotoluene hemi-solvate.
The Table below is a summary of samples isolated from this controlled cooling experiment and the XRPD patterns afforded. Example 31: DVS examination of amorphous 5-MeO-DMT benzoate produced via lyophilisation
5-MeO-DMT benzoate 20/20/150FP2, 150mg, was dissolved in deionised (DI) water, 5ml affording a clear solution. The solution was clarified into a 500ml round bottom flask, the round bottom flask was rotated in an acetone/dry ice bath to freeze the solution in a thin layer around the flask. The ice was sublimed in vacuo at ambient temperature affording a fluffy white solid. The solid was removed from the round bottom flask and transferred to the DVS instrument. During this transfer, the solid collapsed to a sticky gum.
The sample was examined by DVS from 40% RH and cycled between 0%RH and 90%RH twice. XRPD was collected on a portion of the sample post-lyophoilisation and post-DVS examination. The XRPD of 5-MeO-DMT benzoate before DVS analysis revealed an amorphous diffraction pattern which was expected (Figure 88). Figure 88 shows XRPD of 5-MeO-DMT benzoate lot 21-01-078. The DVS examination demonstrates an initial weight reduction of ca. 1.4% from the start of the investigation during the first desorption cycle (Figure 89) which was much lower than the 5 wt% required for a 5-MeO-DMT benzoate monohydrate. Weight reduction continues despite the RH increasing to 70 %RH during the first sorption. At 80 and 90 %RH on the first sorption cycle, there is a small increase in weight. Following this there is a weight reduction to the minimum on the second desorption cycle, on the subsequent sorption cycle there is no change in weight until 50 %RH, between 50 %RH and 90 %RH there is a weight increase of 0.2%.
Figure 89 shows DVS isothermal plot of 5-MeO-DMT benzoate lot 21-01-078. The XRPD of 5-MeO-DMT benzoate lot 21-01-078 after DVS examination at 90%RH revealed a diffraction pattern concordant with Pattern A (Figure 90). Figure 90 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-078 (post-DVS) and 20-37-64. Amorphous 5-MeO-DMT benzoate is unstable and undergoes transformation to Pattern A form under all conditions studied. Under ambient conditions it is believed that the amorphous version uptakes moisture from the atmosphere which is eliminated from the sample following conversion to Pattern A form. Such a conversion is not considered to be via a hydrate as there has been no observed evidence of a 5-MeO-DMT benzoate hydrate. Alternatively, the process of lyophilisation could seem complete when in fact some moisture remains bound to the solid. Upon evacuation of the lyophilisation vessel to atmospheric pressure, the low density, voluminous solid contracts, entrapping the moisture to afford the gum that is then ejected as the amorphous gum and converts to the more stable, ordered Pattern A form version.
Example 32: FTIR spectroscopy of 5-MeO-DMT benzoate Patterns A, B and C
Figure 91 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl). Figure 92 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20- 20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1. Figure 93 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1; spectra separated. Inspection of FTIRs reveals the Pattern A form demonstrates a number of bands of significantly different intensity compared to Patterns B form and C form. Such notable bands were observed at ca. 3130, 1540, 1460, 1160 and 690 cm-1, whilst key absent (or significantly reduced intensity) bands present in Patterns B and C included those observed at ca. 3230 and 1640 cm-1. Patterns B and C forms demonstrated far fewer differences in their FTIRs to one another, as when compared to the FTIR of the Pattern A form. This was anticipated when it is considered that the Pattern C form hemi-solvate desolvates somewhat readily to afford the Pattern B form, resulting in a relatively small change to the crystal lattice compared to the energy required (i.e.; drying in vacuo at elevated temperature) to induce conversion of Pattern B form to Pattern A form, restructuring the crystal lattice to a greater extent than facile desolvation.
Example 33: Stability of Patterns B and C
Drying 5-MeO-DMT benzoate Pattern C form in vacuo at 50°C for 24 hours historically often afforded Pattern B form and Pattern B form is known to transform to Pattern A form at 90°C as observed by hot stage microscopy. The stability of Pattern A form and Pattern B form under both atmospheric conditions and in vacuo at 50°C was investigated to determine the relationship between the forms.
5-MeO-DMT benzoate lot 21-01-071 Cl, Pattern C form, and lot 21-01-071 C2, Pattern B form, were charged to XRPD sample holders and sample vials and left open to the atmosphere for 12 days.
5-MeO-DMT benzoate lot 21-01-071 Cl, Pattern C form, was dried in vacuo at 50°C for 5 days.
XRPD was performed regularly. DSC and 1H NMR spectroscopy were performed on samples where significant differences to the diffraction patterns were observed. The Table below shows a summary of solid form conversion by XRPD during the stability tests.
Example 34: Competitive equilibration of5-MeO-DMT benzoate Pattern A, B, and C forms in solvents
The relationship between 5-MeO-DMT benzoate Pattern A, B, and C forms was investigated to determine the thermodynamically stable version and hierarchy. Competitive equilibration was conducted between Pattern A and B forms, and Pattern A and C forms in a variety of solvents including IPA and toluene. Pattern A form was expected to be the most stable form given its melting point of 124°C and prevalence during most investigations performed.
5-MeO-DMT benzoate 20/20/150FP2, Pattern A form, 15mg, was charged to all crystallisation tubes. 5-MeO-DMT benzoate lot 21-01-071 C2, Pattern B form, 30mg, was charged to AB crystallisation tubes. 5-MeO-DMT benzoate toluene hemi-solvate lot 21-01-071 Cl, Pattern C form, 30mg, was charged to AC crystallisation tubes. Solvent, 0.5ml, was charged to crystallisation tubes as detailed in the Table below. Suspensions were agitated at lOOrpm at 20 ±2°C for 24 hours. Suspensions were isolated via isolute cartridge and air dried for 5 minutes and characterised by XRPD and DSC. The XRPD of all samples revealed the majority gave Pattern A.
Sample AC5 isolated from MEK revealed an additional diffraction at 8.8 °20 however this was considered to be caused by the splitting of the diffraction at 9 °20 due to better resolution between diffractions of this sample.
The DSC thermograph of most Pattern A form samples revealed an endothermic event with peak temperatures ranging from 123.74°C to 124.22°C which is indicative of Pattern A form. The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-079 AB3, isolated from isopropyl acetate, revealed a series of events between 109°C and 115°C, then a minor endothermic event with a peak temperature of 115.69°C. This was followed by a major endothermic event with a peak temperature of 123.85°C indicative of the Pattern A form.
The minor endothermic events are believed to be due to the incomplete conversion of Pattern B form to Pattern A form via equilibration.
The XRPD of 5-MeO-DMT benzoate lot 21-01-079 AB2 and AC2, both equilibrated in toluene, revealed a diffraction pattern concordant with 5-MeO-DMT benzoate lot 21-01-064 A toluene hemi-solvate, Pattern C form.
The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-079 AB2 revealed a bimodal endothermic event with peak temperatures of 114.96°C and 121.92°C. The thermal characteristics are similar to previously isolated pattern C samples, including 5-MeO-DMT benzoate lot 21-01-073 J.
The DSC thermograph of 5-MeO-DMT benzoate lot 21-01-079 AC2 revealed a minor endothermic event with a peak temperature of 110.11°C, followed by overlapping endothermic and exothermic events between 110.73°C and 113.23°C. This was followed by an endothermic event with a peak temperature of 122.82°C, this endothermic event is comparable to the melt of Pattern A form when recrystallised from Pattern B form.
Competitive equilibration of both Pattern A/B form mixtures and Pattern A/C form mixtures in solvents that were not previously observed to produce hemi-solvates demonstrated conversion to the Pattern A form. It is anticipated that all other hemi-solvates will convert to the Pattern A form in these solvents.
Competitive equilibration of both Pattern A/B forms and Pattern A/C forms in toluene demonstrated conversion to the Pattern C form. It is anticipated that equilibration of 5-MeO-DMT benzoate in a solvent (typically an aromatic solvent) that has the propensity to form a hemi-solvate will afford that particular 5-MeO-DMT benzoate hemi- solvate over the otherwise thermodynamically stable Pattern A form solid form version.
Example 35: Administration of a 5-MeO-DMT salt
The physical surroundings of the participant/patient/subject are of high importance in the character of many psychedelic experiences. The space should be private, meaning that there should be no chance of intrusion by others. Ideally, sound from outside (e.g. the hallway, the street, etc.) will be minimal. The dosing sessions should take place in rooms that feel like a living room or den rather than a clinical setting. Artwork, plants, flowers, soft furniture, soft lighting, and related decor should be employed in creating a cozy and relaxing aesthetic. Artwork with any specific religious iconography, ideological connotation, or tendency to evoke negative emotions should be avoided. The dosing room may also provide comfortable furniture for the participant and the therapists, who may sit on either side of the participant. Participants under the effect of 5-MeO-DMT may exhibit spontaneous movement or slide off of the bed or couch in their prone position. It is therefore important to make sure no sharp or hard objects are nearby that the participant may fall on. Additionally, pillows may be useful to physically support participants who are mobile during the experience. A therapist can provide physical support to the participant by placing a pillow between their hands and the participant's body.
Music may accompany the experience, so the dosing room should be equipped with a stereo. The room should shield the participant from sights and sounds of the world beyond the room, and the participant should not have any cause for concern of observation or interruption by anyone other than the therapists.
The space may also contain:
The tools for safety procedures and medical devices necessary to respond in the unlikely event of a medical complication. The participant should be made aware of these procedures and the equipment, but as much as possible they should be hidden from view.
A secured and locked space for study materials and documentation in the session room or nearby.
An approved safe for storing the 5-MeO-DMT in the session room or nearby.
Audio and video-recording equipment: If allowed in the study protocol the participant will have already consented to being recorded, and should be made aware of the equipment, but it should be placed to be as unobtrusive as possible. Participants may request the cessation of recording at any time. Physical Space
The space may be large enough to accommodate chairs for two therapists, the stereo equipment and cabinet for storage of the participant's belongings and any extra supplies the therapists may need during the day. The space may accommodate a bed or couch on which the participant can either sit up or lie down with a comfortable surroundings of pillows. The space may be at least 1002feet or 102 meters so that participants do not feel cramped or too physically close to therapists. Participants should have room to explore a variety of positions including sitting on the floor or stretch their bodies without restriction. A bathroom should be either accessible directly from the session room or nearby.
Music
5-MeO-DMT sessions may use a pre-set playlist of nature sounds for creating a calm atmosphere. These nature sounds are considered to be a background element, helping drown out any noise from outside the room, and keep the participant focused on their experience. Participants are not instructed to listen to the sounds in any particular way, but may be asked to focus on it as a way of grounding their senses and relaxing before or after session.
Medication Discontinuation
Medication discontinuation can be challenging for participants. Participants are to have discontinued all contraindicated medications and completed washout periods prior to Prep-1 with the therapist. The study team members, including the therapist, may provide supportive check-in calls with the participant prior to this, as-needed during the washout period, but should not start Prep-1 until washout is complete and the participant confirms intention to continue with the therapy.
Preparatory Sessions
This treatment model includes three, 60-90 minute preparatory sessions with the therapist. These take place 7 days, 4 days, and 1 day before the 5-MeO-DMT session. Preparatory sessions are designed to take place via telemedicine, but can be in-person if possible.
Preparatory Session 1
The following topics may be covered in the first preparatory session.
Getting to know the participant
The therapist will spend some of the preparation session time getting to know the participant. The therapist may ask open-ended questions about:
How they found out about the treatment and what their expectations are;
Current life situation with regards to living situation, work, school, and important relationships; Understanding of their own depression;
Key life events that the participant feels might be of relevance
The therapist should be listening for how the participant talks about themselves and their relationship to their depression, how they relate to the therapist and study environment, and stay attuned to establishing a sense of trust and rapport with the participant. Clinical impressions of difficulty forming a trusting relationship with the therapist or any other clinical factors that could interfere with the participants' ability to engage in the treatment should be noted and discussed with the study team. Although in the preparatory session stage, the therapist may learn more of the participant that could be reasons for study exclusion.
Establishing the role of the therapist
Therapists in the 5-MeO-DMT-assisted therapy treatment model form a relationship with study participants which becomes part of the container in which the 5MDE (subjective experience of 5-MeO-DMT) takes place. This formation of this relationship is deliberate on the therapist's part and characterized by the therapist establishing transparency and trust, taking clinical responsibility for the patient's wellbeing, and relational and emotional safety for the patient. The therapeutic relationship is understood as a critical component of the set and setting for the therapeutic use of the 5MDE. The communication and establishment of this relationship is both explicit (overt) and implicit (covert) in the therapists behaviours and mannerisms throughout the treatment. Explaining the therapeutic model with participant as active participant in their process
The therapist should explain the therapeutic model used in this research study to the participant in the first preparation session. The explanation should include:
Practical considerations/aspects:
How many meetings with the therapist will occur, and for how long.
That the therapy is thought to work by:
Creating a safe container for the experience so that the participant knows what to expect and can fully let go into their experience,
Helping the participant focus on and explore their own responses to the experience,
Facilitating a process of the participant determining for themselves how they will put their insights into practice in their life.
That the therapist's role is:
Supporting the participant through the session, engaging in a series of activities to elicit the participant's unique experience and insights, fostering the participant's process of implementing the resulting changes in their life.
That the therapy is:
Not a full deep dive into participant's personal history, not a place to do specific problem solving or engage in CBT, Psychodynamic interpretations, get general advice, or receive other interventions the participant may be familiar with.
Establishing physical, emotional, and psychological/relational safety
Beginning in the first preparatory session the therapist establishes the environment of physical, emotional, and psychological safety. The therapist explains the safety of 5-MeO-DMT and the safety procedures relevant to the participant's physical health for the session. With regards to emotional safety the therapist states that all emotional experiences are welcomed, that there is no area of experience that the participant is not welcome to share. Safety can also be established through the calm reassuring presence of the therapist, which does not always require the use of language.
The use of self-disclosure is not prohibited, but should be used very sparingly. A participant may be seeking safety by asking personal questions of the therapist. If the therapist chooses to disclose, it should be brief and under the condition the participant share why this personal information is important to them.
Psychological/relational safety is established by assuring the participant that their wishes will be respected with regards to the use of touch. Also, the participant is to be reassured that if they choose not to participate in the 5MDE experience they may do so at any point up until drug administration and that this will be respected, and that the therapy sessions will still be available to them if they make that choice.
The therapist can use the following techniques to establish safety with the participant:
Ask open-ended questions that invite the expression of doubts, hesitancies, or concerns:
What questions do you have for me?
What more would you like to know about 5-MeO-DMT?
What would you find helpful in the event ... ?
How could I be of assistance to you if you feel ... ?
Encourage and engage with the full range of participant's emotions and experiences without trying to fix or resolve them:
Participant expresses skepticism about the 5-MeO-DMT Experience: I appreciate you sharing that doubt with me. What do you make of that in light of your presence here at this time?
Participant expresses fear about the 5MDE Experience: What more can you tell me about your fear and how it manifests for you? How could I be helpful to you as you experience this?
Use affirmations to establish an environment of valuing the participant's time and effort: I really appreciate the time you are putting into this treatment and your willingness to participate in research.
Your experience is unique to you and I appreciate the opportunity to see you through this process.
Expected potential subjective drug effects (unity, "feeling like dying", "the void",)
It may be helpful to discuss the concept of "non-ordinary state of consciousness" with participants. In the past, "altered state of consciousness" was often associated with experienced engendered by psychedelic compounds. However, alterations of consciousness are experienced on a daily basis, as moods or feelings shift, or when people shift from awake alertness to feeling tired and drowsy. "Non-ordinary state of consciousness" emphasizes the quality of an experience that is not ordinarily had on a daily occurrence, but can still be within human experience.
The therapist may begin this conversation by asking the participant about their existing knowledge of 5-MeO-DMT effects, and listen for specific expectation or ideas about it. The therapist is to encourage an attitude of openness toward the experience, encouraging participants to explore what kinds/ideas they may have and be open to the possibility that it will not be possible to imagine what this will be like. Participants may have specific expectations based on the media, prior experience with 5-MeO-DMT or other psychedelics, or other kinds of non-ordinary states of consciousness. It is important for therapists to provide a balanced description of what the participant may experience.
Different people have different levels of comfort with "not knowing" what something will be like, or what to expect. The therapist may explore the participant's level of comfort with the unknown, their relationship to the idea the future not being fully knowable in any situation, and how they generally relate to this. Among participants with depression there may be deep fear of the unknown, anticipation of what is expected in the future (more negative experiences), resulting in a feedback loop of feeling fearful and depressed. Therapists should elicit and explore this area during preparation.
Common 5-MeO-DMT Experiences: The therapist should also introduce a few key terms and commonly reported experiences known to occur under 5-MeO-DMT. These include a feeling of unity, a feeling of dying, and a feeling of entering or experiencing a "void" (absence of material reality). Some participants may have an existing spiritual, philosophical, or religious belief system through which they will interpret or make meaning of these experiences. Therapists should enquire about this and work with the participant's own explanation and terms, without taking a stance as to whether these are correct or erroneous.
Social Support and Social Media
Participant's social support may be assessed during preparation sessions and be determined by the therapist to be adequate to support the patient through the process of change, especially in the event of either disappointment or dramatic symptom reduction. In the event the participant has a psychotherapist outside of the study the study therapist may, with the participant's permission, have a phone call with the participants therapist to describe the nature of the study and therapeutic approach and answer any questions the therapist may have. The study therapist may also educate any friends or family members who are close to the participant and have questions regarding the nature of the study, the 5-MeO-DMT experience, and what to expect. The therapist should discuss social support with the participant including preparing the participant for the variety of reactions their friends and family may have.
Therapists may advise participants to take caution around posting about their experience on social media so as not to elicit excessive public commentary. Inadequate social support or use of social media in a way that may be disruptive to the therapeutic process may be discussed and resolved prior to 5-MeO-DMT administration.
Preparatory Session 2
The following topics may be covered in the second preparatory session.
Drug experience preparation: trust, surrender (let go), embrace, transcendence.
There are several key attitudes towards psychedelic experiences that are considered to be conducive to a positive and clinically helpful experience. The more participants can embody a relaxed stance toward their experience the less likely they are to struggle, inadvertently creating a loop of stress and distress that heightens attention to negative aspects and interpretations. The therapist may educate the participant on the purpose of deliberately generating an attitude of trust, surrendering to the experience, and letting go of attempts to control the experience. Therapists may encourage participants to develop an attitude of welcoming and embracing all experiences they may have as part of their 5-MeO-DMT experience. The therapist may suggest to a participant that all aspects of the experience (feelings, sensations, and thoughts) can be welcomed. Previous research with psychedelics has demonstrated that a capacity to be absorbed by the experience can contribute to the potency of a mystical experience.
The Drug Administration
The therapist should explain that on the day of the session that a member of the research team will enter the room briefly to administer the study drug. The therapist should explain the participant positioning, e.g. they will be in a seated position on the bed or couch, that the research team member will insert the nasal spray device in one nostril, and that they will be asked to allow the therapist to assist them in lying down on the bed or couch immediately afterward.
Session procedures including boundaries, use of touch, safety, etc.
The therapist will explain the process of the session. The session is contained by the timing of the dosing and the physical environment of the dosing room. It begins when the participant enters the room and engages with the therapist in the Session Opening. Session Opening is a formal moment in which the participant and therapist sit together in the room, all preparations having been made, and playlist started. The therapist may lead a breathing exercise of the participant's choice, if the participant is open to engaging in one, and ask the participant to reflect on the values they choose in the preparation session, or any other value or intention that is important to them. Once the participant signals that they are ready, a member of the research team will administer the nasal spray to the participant. Trust and safety are not only communicated verbally, but also this may be nonverbally through how a therapist holds themselves in the presence of the participant. If a therapist is overly anxious, or fearful, this may be felt by the participant. It is important that the therapist is centered throughout the dosing session, particularly at times when a participant is expressing intense affect, unusual somatic expressions, or is asking for support.
Somatic changes and shifts in one's sense of their body
Some participants may experience an intensified awareness of their body such as feeling their heart rate more strongly or physical sensations in their temple. Other participants may be aware of a tingling in their body, changes or perceived difficulty breathing, or other unusual physiological experiences. It is important for the therapist to communicate that these changes in perception are normal and should not be a focus of preoccupation or fear. If these sensations arise, the participant should be encouraged to communicate these to the therapist, if they so desire. The therapist should reassure the participant that these sensations are expected and are normal to have. The therapist can inform and remind the participant that naturally occurring 5-MeO-DMT has been consumed in other settings for hundreds of years with no indication that it is physically harmful, and that these changes are expected and will resolve shortly.
Discussing expectations and intentions
Expectations can be defined as mental representations and beliefs of how something in the future will be. Sometimes expectations can be explicitly identified, and sometimes they are subperceptual, taken for granted. Both kinds of expectations may be important to treatment. The therapist should ask about explicit expectations and encourage the participant to acknowledge and set these aside such that they do not engage in comparing their experience to expectations. The therapist is also listening for subperceptual expectations that may come into awareness through the therapy. Intentions are ways of relating to a behaviour or experience. In the 5-MeO-DMT treatment, it can be important for the therapist to elicit and understand the participant's intentions as these can vary greatly and may be taken for granted. Therapists are to engage participants in a process of identifying and setting their intentions such that these are explicit and can be referenced later in integration. The purpose of the intention is for it to be identified and then let go of, with the knowledge that it can be part of the 5MED.
Recurrence of acute effects
Some individuals who used 5-MeO-DMT in non-clinical contexts have reported re-experiencing 5-MeO-DMT's subjective effects in the days after. The dose used, purity, and other factors were not monitored in these cases. The likelihood of these reactivations occurring in a controlled clinical study context is not known, but estimated to be less likely. Nonetheless, it is important for participants to be made aware of this phenomenon. The experience of reactivations are often reported as pleasant, brief (lasting a few moments to minutes), and do not occur with enough frequency to interfere with a person's life. These reactivations are thought by some as part of the integration process. If a participant notices certain activities trigger reactivations, such as certain meditative states, stimulants, or other drugs, and the participant finds these reactivations unpleasant, it should be suggested to the participant that they avoid such triggers. Processing the 5-MeO-DMT experience in therapy, as part of integration, may also be helpful.
Discussing the use of touch
Therapists in this modality may engage in two types of touch: therapeutic touch, and touch for safety reasons. During preparation the therapist should explain and define each. Therapeutic touch is touch that is intended to connect with, sooth, or otherwise communicate with the participant for therapeutic aims. It is always fully consensual, non- sexual, and the participant is encouraged to decline or cease therapeutic touch at any time. Touch for safety reasons can include supporting a participant who is having trouble walking by offering an arm to hold, or blocking a patient back from leaving the room while under acute drug effects. This touch is agreed to in advance, is always non-sexual, and limited to specific safety concerns. Therapists should discuss both of these and establish boundaries with participants ahead of session.
Preparing for after the session (what to expect, what to do, setting aside time for integration)
Participants should be encouraged to take some time to rest and integrate their experience after their session day. Study therapists should ask participants to plan for time off after their session, at least the full day of the session and the day after the session. Therapists should explain that after the acute effects of the 5-MeO-DMT have worn off they will stay together in the room for a while. This period of time will be for the participant to readjust to their experience after the acute effects. They will be asked to share what they can recall about their experience and any reactions they have. They will not be asked to share anything they don't want to share, and are welcome to keep their experience private. They may choose to write or draw about their experience, art supplies and writing supplies will be available. They may be encouraged to spend some time continue to stay with their experience, with the therapist's support, for around an hour. They will then meet with the study team for a safety assessment before going home. Once at home they are encouraged to rest and continue to stay with the experience and the insights, ideas, or new understanding they may have from it. Participants should be reminded that they do not need to share their experience with others unless they want to, and are encouraged to continue to focus on it in whatever way they find most helpful. Participants should refrain from returning to work, from driving, drinking alcohol, drug use, or being a sole caregiver for a child or dependent for the rest of the day.
Therapist teaches Breathing Exercise for dosing session
When stressed, breaths become shorter and shallower, and when relaxed, the breath becomes longer and slower. Working with the breath is a way of modulating and regulating one's mental state. The therapist may teach and practice two breathing techniques with the participant. These are designed to help the participant relax their body and mind, tolerate stressful or uncomfortable experiences, and develop autonomy through practice on their own. These are not for use during the acute effects of 5-MeO-DMT, but can be used prior to dosing and afterward.
When teaching the practices, the therapist elicits the participant's individual response to each practice to assess suitability of using it. Breathing practices include: Balancing Breath, Diaphragmatic Breath and Counted Breath.
Preparatory Session 3
Values card sort with prompts
The therapeutic protocol may use a customized Personal Values Card Sort to assist with the therapeutic focus on shift in sense of self. This is done by asking about how people relate to their chosen values before the session, and how they relate to them afterward, drawing attention to shifts, changes, and using these as a guide for the kind of changes the participant may desire to make. It is used as a way to elicit conversation about the participant's sense of self, beliefs about self, and changes in those senses/beliefs throughout the therapy. Therapists may engage participants in the card sort exercise in the third preparation session such that it occurs 1-2 days before the dosing session.
The Values Card Sort Instructions are:
1. Place five anchor cards in order from 1-5 in front of the participant from left to right in order of least to most important.
2. Shuffle the 100 value cards; keep the 2 blank cards separate. 3. Instruct the participant to sort the cards using the following script: "/ placed five title cards in front of you— not important to me, somewhat important to me, important to me, very important to me, most important to me. I'm going to give you a stack of 100 personal value cards. I would like you to look at each card and place it under one of the five title cards. There are also two blank cards. If there is a value you would like to include, write it on the card and put it in whichever pile you would like. I would like you to sort all 100 cards, but whether you use the two additional cards is optional. Do you have any guestions?"
4. When the participant is finished sorting, thank them and invite them to look at the "most important" category, removing the other cards from the table.
5. Read the following: "For the second task, I'd like you to focus on the top values you put in the "most important" category and choose the top five."
6. When the participant has chosen their top five cards, thank them read the following: "For the third task, I'd like you to focus on the top five values you chose and rank them in order from most to least important."
7. When the participant indicates they are finished ordering, check to make sure you understand how the cards were sorted (ascending or descending). Point to the #1 spot and say, "I want to make sure I have this right— is this your number one value?"
8. Record values on a scoring sheet, journal or by taking a picture of the cards. Participants should keep a record of their card selections as well.
Debriefing and discussion:
Next, invite the participant to engage in a structured discussion of each value using a few of the following open- ended prompts, or similar prompts depending on the context of your work:
You selected as your # value?
Please tell me more about what means to you?
What are some ways has been represented in your life?
What are some ways you'd like to see more of in your life?
How does your decision to or not relate to this value?
How much would you like to have in your life?
How would you know if was increasing or decreasing in your life?
How does relate to the change you are trying to make (or considering making)?
Invite the participant to journal about their answers to the same questions with the remaining cards afterwards. In later sessions it can be helpful to check in on the values and revisit these questions, see how answers have changed, and how participants are currently relating to their values.
Assistant Therapist
The session may be conducted by the therapist with an assistant therapist such that a second person is available to assist in case of any adverse event or physical complication in the participant's safety. The assistant who will be present for the session should be introduced in Prep Session 3 and included in a conversation such that they get to know the participant.
Session-Specific Therapeutic Tasks
Therapists should aim to complete the therapeutic tasks outlined above according to the chart below, while acknowledging that some variation will occur based on individual participant needs.
5-MeO-DMT Experience Session
The therapist is present with the participant during the session — including pre-experience and post-experience times. This is the only session that must be conducted in-person. The site and therapist should schedule about 3 hours for the session, including pre-experience and post-experience time. This does not include the time allotted to engage in baseline measures and enrolment confirmation prior to the session. Local regulatory approvals will determine the minimum length of time a participant must be under observation following 5-MeO-DMT administration.
Pre-experience (Around 30 Minutes)
After the participant has completed all enrolment confirmation and randomization procedures and is cleared to participate, the Therapist, Assistant Therapist, and participant together in the room review all aspects of the room and safety procedures. The therapist should introduce the participant to the team member administering the 5- MeO-DMT, to create a sense of familiarity. Therapist introduces any Assistant Therapist and reviews safety features of the room and the equipment present. Participant has time to ask any questions. The therapist will ask about any responses to the situation and how the participant is feeling about their session. The participant should not be rushed into the dosing by the therapists. The therapist will ask the participant to engage in a period of relaxation prior to dosing. Participant will be asked to lie down, close their eyes, listen to the music, and, if willing, engage in at least one of the breathing exercises with the therapist's guidance. When the participant is settled and comfortable, the therapist will initiate the Session Opening. This practice helps contain and emphasize the specialness of the experience. Therapists will contact the member of the research team to come to the room and administer the 5-MeO-DMT. The team member should be aware not to disrupt the peaceful atmosphere of the room. The participant should be in a seated position when insufflating the 5-MeO-DMT, as the effects may be felt quickly, the participant should be transitioned to a prone position and remain prone for the duration of the effect of the 5-MeO-DMT.
Experience (Around 60 Minutes)
It is expected that the onset of acute effects will occur very rapidly after administration. Therapists should be aware of the time of administration so they can be aware of the participant's response in relation to the expected course of duration. Some participants may want to know how long they experienced the effects of the 5-MeO-DMT and it is appropriate to share this information if asked. A significant portion of the time the participant may be nonverbal, focused inward, and engaging in their experience. It is important for the therapist to be mindfully aware of the participant, but not interfering with the participant's experience, unless it is clear that participant is seeking the therapist's support. Therapists are encouraged to engage in self-regulation techniques while the participant is undergoing their experience. This may be in the form of slow intentional inhaling and exhaling, or any other activity that helps the therapist ground and self-regulate. This is both for the therapist's benefit, as well as the participants', because a participant in a heightened non-ordinary state may be particularly attune to or pick up on their therapist's anxiety. It is optimal for the therapist to follow the participant's lead when choosing to verbally engage as the 5- MeO-DMT experience appears to be subsiding. Therapists may be eager to ask the participant about their experience, but it is preferable to wait until the participant is ready to share on their own. A participant may wish to remain in a period of silence, even after the apparent acute 5-MeO-DMT effect is gone. It is appropriate for therapists to greet participants with a friendly smile and welcoming nonverbal behaviour, and allow participants to take the lead on sharing when they feel ready.
Post-experience (around 90 minutes)
Therapist will encourage the participant to stay with their experience for a period of time of at least one hour after the acute effects of the 5-MeO-DMT have worn off and the participant is once again aware of their surroundings and situation in the treatment room. To stay with the experience means to continue directing attention toward it in whatever way feels most appropriate to the participant, without turning to engagement in distractions, entertainment, or the concerns of daily life. During this time the therapist will invite the participant to describe their experience, if they choose to, and respect the choice not to if the participant is unready. If the participant does describe their experience the therapist is to listen and encourage the participant to express whatever they would like to share without interpretation or attempts to make meaning. The therapist practices simply listening, encouraging the participant to describe what they can about the experience. The therapist also offers the participant the option of resting and listening to the music, or to write about or draw any aspects of the experience they desire. At the end of this time period, the therapist will verify with the participant that they feel ready to close the session, will engage in the Session Closing, and contact the study team for exit assessment.
Integration Sessions
The key principle of integration sessions is to help the participant focus on shifts in their perception of themselves and the implications of these as they relate to their depression. Self, for the purpose of this study, is broadly defined as the narrative or historical self, the sense of a coherent "I" that moves through experiences, and the self-identities one may use. It is key to remember that the sense of self, or the "I," is reflected in both the experiencer's selfexperience and experience of the object of experience, therefore descriptions may, on the surface, be of changes in the perception of the external world, but reflect shifts in the internal processes. To this end, the following therapeutic tasks will guide the integration sessions.
These sessions are less structured than preparatory sessions to accommodate variations in participant responses. There are three tasks: The first should occur at all sessions, the second and third may be introduced and engaged in if and when the participant is ready and willing. The tasks are:
Listening and hearing about the participant's experience
Therapists ask open-ended questions about the participant's experience and listen with non-judgmental curiosity to the participant's descriptions. Therapists ask only that participants focus on the 5MDE and related material, such that their time together is focused on the treatment. Therapists should focus inquiry on the participant's experience, asking them to tune into any aspect of the three types of sense of self they can identify.
Reintroducing the values and discussing relationship to each
The therapist will reintroduce the values identified in the Values Card Sort from preparation and bring discussion back to them if and when appropriate in the integration sessions. There is by no means a requirement to engage in the structured discussion of the values, but it serves as a framework where needed to direct the focus of sessions toward participants' shift in sense of self.
The therapist may ask for example, to reintroduce the values:
Therapist: Before your 5MDE we discussed a list of Values you hold and how you were relating to each of those. I'd like to draw our attention back to that and ask for a little detail about how those ways of relating might have shifted. For instance you named "Family" as one thing that was important to you, but you were concerned that you weren't feeling well enough to be present for family relationships. You said you were isolating from your family a lot by working on your computer from your makeshift office in the garage every evening. How do you relate to the value of "Family" now?
In the dialogue, the therapist can for example continue to focus on shifts in how the participant is relating to his value of "Family" by enquiring about what he is noticing in this area. Create ways the participant can act to enhance their relationship to their chosen values; identify value-oriented action in their life as an integration practice. Integration can be understood as a process of embodying or living out the insights one has. In at least one of the integration sessions, the earliest the therapist feels the participant can engage in this stage, the therapist should introduce the idea of identifying value-oriented actions they can take in their lives as integration practices. Explaining the concept as above, the therapist can invite the participant to recall the values they identified (or any other that is important to them), recall the insights or experiences of their 5-MeO- DMT session, and think creatively about things they might try intentionally doing differently in order to implement positive change in their relationship to the values based on those insights and experiences
Items:
1. A method of administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient who is diagnosed with depression, the method comprising:
• the discontinuation of the use by the patient of any mood-altering substance or any other substance, medications or preparation which may affect serotonergic function;
• the relaxation of the patient, such as the patient is instructed to lay down, close their eyes, and listen to music and/or engage in one or more breathing exercises guided by a therapist;
• optionally, the clearing of their nasal passages, by blowing their nose, by the patient e.g. whilst sat down;
• the administration of 5-MeO-DMT, optionally by via insufflation, and optionally wherein the patient is in a prone position for the duration of the effects of 5-MeO-DMT.
2. The method of item 1, wherein the patient has discontinued the use of monoamine oxidase (MAO) inhibitors, CYP2D6 inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), lithium, antipsychotics, triptans, tramadol, 5- hydroxytryptophan, herbal preparations which may contain 5-HTP, St John's Wort and any benzodiazepines prior to administration of 5-MeO-DMT.
3. The method of item 1 or item 2, wherein the 5-MeO-DMT is administered via the Aptar Unidose (UDS) liquid delivery system.
4. The method of item 1, item 2 or item 3, wherein the 5-MeO-DMT is the benzoate salt, optionally a polymorph of the benzoate salt.
5. The method of any one of items 1 to 4, wherein the patient participates in at least one psychological support session before administration of the 5-MeO-DMT.
6. The method of item 5, wherein the patient participates in at least three psychological support sessions before administration of the 5-MeO-DMT.
7. The method of item 6, wherein the patient participates in three psychological support sessions, wherein these sessions take place 7 days, 4 days and 1 day before the administration of the 5-MeO-DMT.
8. The method of any one of items 5 to 7, wherein the psychological support sessions are 60-90 minutes in length.
9. The method of any one of items 5 to 8, wherein at least one therapeutic intention is discussed during the psychological support session.
10. The method of any one of items 5 to 9, wherein self-directed inquiry and experiential processing are practiced during the psychological support session.
11. The method of any one of items 1 to 10, wherein the patient participates in at least one psychological support session after administration of the 5-MeO-DMT.
12. The method of item 11, wherein the patient participates in at least three psychological support sessions after administration of the 5-MeO-DMT.
13. The method of item 11 or item 12, wherein the patient participates in three psychological support sessions, wherein these sessions take place 1 day, 4 days and 7 days after the administration of the 5-MeO-DMT.
14. The method of any one of items 11 to 13, wherein the psychological support sessions are 60-90 minutes in length.
15. The method of any one of items 1 to 14, wherein the 5-MeO-DMT is administered to the patient in a room with a substantially non-clinical appearance.
16. The method of item 15, wherein the room comprises soft furniture.
17. The method of item 15 or 16, wherein the room is decorated using muted colours.
18. The method of any one of items 15 to 17, wherein the room comprises a high-resolution sound system.
19. The method of any one of items 15 to 18 wherein the room comprises food and drink for the patient and therapist. 20. The method of any one of items 15 to 19 wherein the room comprises an approved safe for storing 5-MeO- DMT.
21. The method of any one of items 15 to 20 wherein the room is insulated such that the patient is shielded from sights and sounds of the world beyond the room.
22. The method of any one of items 15 to 21 wherein the room does not contain any artwork or decoration with any specific religious iconography, ideological connotation, or other such artwork or decoration which may evoke negative emotions in a patient.
23. The method of any one of items 15 to 22, wherein the room comprises a bed or a couch.
24. The method of item 23, wherein the patient lies in the bed or on the couch for approximately 0.5-8 hours, or a substantial fraction thereof, after administration of the 5-MeO-DMT.
25. The method of any one of items 1 to 24, wherein the patient listens to music for approximately 0.5-8 hours, or a substantial fraction thereof, after administration of the 5-MeO-DMT.
26. The method of any one of items 1 to 25, wherein the patient wears an eye mask for approximately 0.5-8 hours, or a substantial fraction thereof, after administration of the 5-MeO-DMT.
27. The method of any one of items 1 to 26, wherein a therapist provides psychological support to the patient for approximately 0.5-8 hours after administration of the 5-MeO-DMT
28. The method of any one of items 1 to 27, wherein the therapist uses guided imagery and/or breathing exercises to calm the patient and/or focus the patient's attention.
29. The method of any one of items 1 to28, wherein the therapist provides reassuring physical contact with the patient.
30. The method of item 29, wherein the therapist holds the hand, arm, or shoulder of the patient.
31. The method of any one of items 1 to 30, wherein the therapist encourages the patient to perform selfdirected inquiry and experiential processing.
32. The method of item 31, wherein the therapist reminds the patient of at least one therapeutic intention.
33. The method of any one of items 1 to 32, wherein the therapist counsels the patient to do one or more of the following:
(1) to accept feelings of anxiety,
(2) to allow the experience to unfold naturally,
(3) to avoid psychologically resisting the experience,
(4) to relax, and/or
(5) to explore the patient's own mental space.
34. The method of any one of items 1 to 33, wherein the therapist does not initiate conversation with the patient.
35. The method of item 34, wherein the therapist responds to the patient if the patient initiates conversation.
36. The method of any one of items 5 to 35, wherein psychological support is provided remotely to the patient.
37. The method of item 36, wherein the psychological support is provided via a digital or electronic system.
38. The method of item 37, wherein the digital or electronic system is a mobile phone app.
39. The method of item 38, wherein the digital or electronic system is a website.
Example 36: Mouse Forced Swim Test
This study aimed to assess the effect of 5-MeO-DMT Benzoate at three doses in the mouse Forced Swim Test (FST). The forced swim test is a model of behavioural despair and is sensitive to detection of various classes of antidepressant drugs.
Housina and Acclimation
Animals received a 72-hour period of acclimation to the test facility prior to the commencement of testing. Animals were housed four per cage in polycarbonate cages bedded with %" bed-o'cob. Cages were changed, and enrichment provided according to standard operating procedures. Animals were maintained on a 12-hour light/12-hour dark cycle with all experimental activity occurring during the animals' light cycle. All animal use procedures were performed in accordance with the principles of the Canadian Council on Animal Care (CCAC).
Food and Water
Certified Rodent Diet (LabDiet® 5001) was offered ad libitum. Animals were not fasted prior to, or after the experiment was initiated. Water was provided ad libitum in glass bottles with stainless steel sippers. Study Design
Test Subjects
Male CD-I mice from Charles River Laboratories (St. Constant, Quebec, Canada) served as test subjects in this study. Animals generally weighed 25-30 g at the time of testing.
Schedule of Events
Treatment Groups
Animals were randomly allocated into the following treatment groups:
Pre-FST Behavioural Test
On day 0, in addition to the forced swim test animals were evaluated for signs of 5- HT (serotonin) syndrome. Animals were exposed to activity chambers for 10 minutes at two timepoints post dose: (1) 5-15 minutes post dose, and (2) 2.5 hours post dose.
Forced Swim Test
Male CD-I mice received the appropriate dose of vehicle, test article, or positive control (treatments summarized above). Following the appropriate pre-treatment time, animals were gently placed into tall glass cylinders filled with water (20-25°C). After a period of vigorous activity, each mouse adopted a characteristic immobile posture which is readily identifiable. The swim test involves scoring the duration of immobility. Over a 6-minute test session, the latency to first immobility is recorded (in seconds). The duration of immobility (in seconds) during the last 4 minutes of the test is also measured. Activity or inactivity from 0-2 minutes is not recorded.
Test Articles
5-MeODMT Benzoate
BEW: 1.59 (Benzoate salt form)
MW: 340.40 g/mol
Doses: 0.5, 1.5, 5 mg/kg (doses corrected to base)
Route of administration, dose volume: SC., 10 mL/kg
Pre-treatment time: 3 hr
Vehicle: 0.9% Saline
Imipramine
BEW: 1.13 MW: 280.415 g/mol
Doses: 30 mg/ kg (doses corrected to base)
Route of administration, dose volume: IP., 10 mL/kg
Pre-treatment time: 3 hr
Vehicle: 0.9% Saline
Results
At 3-hour post-dose, over the 6-minute test session, there is a positive trend in reducing the duration of immobility and increasing latency to immobility by the low doses of 5-MeO-DMT benzoate (0.5 and 1.5 mg/kg), compared to vehicle-treated mice (time immobile 2-6 minutes, vehicle: 190.4 ± 7.7 seconds - 5-MeO-DMT benzoate: 133.2 ± 24.9 seconds (0.5 mg/kg), 137.6 ± 17.0 seconds (1.5 mg/kg), 156.8 ± 18.7 seconds (5 mg/kg) - Imipramine 46.8 ± 16.6 seconds, Figure 94. Latency to immobility, vehicle: 95.5 ± 4.6 seconds - 5-MeO-DMT benzoate 121.8 ± 22.0 seconds (0.5 mg/kg), 120.9 ± 13.3 seconds (1.5 mg/kg), 85.0 ± 9.5 seconds (5 mg/kg), imipramine 268.6 ± 30.3 second, Figure 95).
Example 37: Study 5MEO-TOX-PK-DOG
The objective of this toxicokinetic study was to assess and compare the toxicokinetic profile of the test items, 5- MeO-DMT-HCI (in a vehicle of 0.1% metolose, Group 2) and 5-MeO-DMT-benzoate (in a vehicle of 0.2% metolose + 0.01% BZK, Group 4).
On day 1, the vehicle or active test item formulations were administered to male Beagle dogs intranasally, at a dose level of 0.4mg/kg in the active groups (corresponding to freebase). Following administration, a series of blood samples was collected from each dog at the following time points: pre-dose (0), 2, 5, 8, 10, 15, 30 and 60 minutes, and 2- and 8-hours post-dose. Plasma samples were analysed for quantification of concentration of 5-MeO-DMT in each sample using a validated method.
5-MeO-DMT was not detected in any of the samples collected from the control animals on Day 1 (not shown). Peak plasma exposure levels (Cmax) were reported at 16.4ng/mL and 35.4ng/mL, for Groups 2 and 4, respectively (see table below). Figure 96 presents the time-course plot of mean plasma concentrations, which shows a broadly comparable TK profile between the HCI and benzoate salt formulations.
Mean Cmax values for 5-MeO-DMT in groups 2 and 4 on day 1
See also Figure 96 which shows 5-MeO-DMT Group Mean Plasma Concentration (ng/mL) in Male Beagle Dogs - Group 2 (the 5-MeO-DMT HCI salt formulation) and Group 4 (the 5-MeO-DMT benzoate salt formulation) - Dose Level (0.4 mg/kg); wherein the Mean Plasma Concentration of Groups 2 and 4 are substantially the same with dose time. Example 38: Further Embodiments
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by an XRPD pattern as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by one or more endothermic events in a DSC thermograph as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by TGA thermograph as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by a DVS isotherm profile as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by a crystalline appearance as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by a particle size distribution as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate as characterised by a FITR spectra as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a polymorph of 5-MeO-DMT benzoate produced as previously or subsequently described. In one embodiment, there is provided a method of producing a polymorph of 5-MeO-DMT benzoate as previously or subsequently described.
In one embodiment, there is provided a composition comprising a polymorph of 5-MeO-DMT benzoate as previously or subsequently described.
In one embodiment, there is provided a 5-MeO-DMT benzoate solvate as characterised as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided a 5-MeO-DMT benzoate hemi-solvate as characterised as substantially illustrated in any one of the Figures or as previously or subsequently described.
In one embodiment, there is provided the use of any previously or subsequently described form of 5-MeO-DMT benzoate in any previously or subsequently described method of treatment.
Herein disclosed is the use of a composition as herein described for the manufacture of a medicament for the treatment of any one of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders.
Herein disclosed is a method of treating any one of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti- inflammatory treatment, depression, treatment resistant depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic in a patient by the administration of a composition as described herein.
Example 39: Pattern H
Further characterisation work has revealed the existence of an additional Pattern H. This Pattern is demonstrated to be metastable and to undergo conversion to Pattern A via solvent equilibration.
The equilibration of multiple polymorphic variants of a solid in a range of favourable solvent systems with temperature modulation is an accepted approach to investigate the relationship between polymorphs and deduce thermodynamically preferred polymorphs or preferential solvent systems for metastable, solvated/hydrated or kinetically favoured versions.
5-MeO-DMT Benzoate versions Form I (Pattern A), Pattern B and Pattern H (ca. 20 mg of each) were charged to crystallisation tubes fitted with stirrer bead agitation, and subjected to equilibration in selected favourable solvent systems for each version of varying chemotypes (600 pl, 10 volumes).
A set of Pattern B and Pattern H samples (ca. 20 mg of each) were also amassed in the same set of solvents (400 pl, 10 volumes) to assess the proposition that there might be an enantiotropic relationship between Pattern B and Pattern H.
The samples were then agitated at 25°C before sampling the solids via filtration for XRPD analysis for form fate after ca. 16 hours of agitation. The solid charges, solvents employed and form classification of the isolated solids following competitive equilibration is described in the Table below.
In an embodiment, Pattern H is characterised by an XRPD as substantially illustrated in Figure 97. In Figure 97, lots 8006740000 and 8006740000 PSR (particle size reduced) are Pattern H, 5520-5-2 and 5520-5-2 PSR are Pattern A, 19-29-115 A is Pattern H but 19-29-115 A PSR is a mixture of Pattern H and Pattern A and 19-29-118A and 19-29- 118A PSR are Pattern H. In an embodiment, Pattern H is characterised by a succinct melt-endo-exo crystallisation event from Pattern H to Pattern A at a l°C/Min heating rate. In an embodiment, Pattern H is characterised by a DSC thermograph as substantially illustrated in Figure 98. In an embodiment, Pattern H is characterised by a DSC thermograph as substantially illustrated in Figure 99. In an embodiment, Pattern H is characterised by a DSC thermograph as substantially illustrated in Figure 100. In an embodiment, Pattern A is characterised by FTIR spectra as substantially illustrated in Figure 104. In an embodiment, Pattern H is characterised by FTIR spectra as substantially illustrated in any one of Figures 101,102 and 103. In an embodiment, Pattern H is characterised by highly coloured large crystals >200 microns. In an embodiment, Pattern H is characterised by irregularly shaped blue coloured small crystals ca.20-100 microns. In an embodiment, Pattern A is characterised by rhombic shaped non birefringent large crystals ca. 400 microns. In an embodiment, Pattern H is obtained following manufacture of 5- MeO-DMT benzoate in isopropyl acetate.
Example 40: Formulations
Sub-lingual
In an embodiment, there is provided a sub-lingual formulation comprising 5-MeO-DMT benzoate. In an embodiment, the sub-lingual formulation is a fast-dissolve sub-lingual formulation. In an embodiment, the sub-lingual formulation is produced by freeze-drying/lyophilisation. In an embodiment, the sub-lingual formulation is produced by:
Formulation of 5-MeO-DMT benzoate into a liquid solution or suspension;
Filling pre-formed blisters with said liquid;
Passing said blisters through a cryogenic freezing process; and
Transfer of said blisters to a lyophilizer followed by lyophilisation.
In an embodiment, passing said blisters through a cryogenic freezing process controls the size of ice crystals. In an embodiment, the sub-lingual formulation disintegrates in less than 30 seconds from coming into contact with saliva. In an embodiment, the sub-lingual formulation disintegrates in 3-10 seconds. In an embodiment, there is provided the use of a sub-lingual formulation of 5-MeO-DMT benzoate in a method of treatment. In an embodiment, there is provided the use of a sub-lingual formulation of 5-MeO-DMT benzoate in the method of manufacture of a medicament for a therapeutic application. In an embodiment, there is provided an orally disintegrating tablet (ODT) comprising 5-MeO-DMT benzoate.
In an embodiment, the ODT is a fast-dissolve sub-lingual formulation. In an embodiment, the ODT is produced by freeze-drying/lyophilisation. In an embodiment, the ODT is produced by:
Formulation of 5-MeO-DMT benzoate into a liquid solution or suspension;
Filling pre-formed blisters with said liquid;
Passing said blisters through a cryogenic freezing process; and
Transfer of said blisters to a lyophilizer followed by lyophilisation.
In an embodiment, passing said blisters through a cryogenic freezing process controls the size of ice crystals. In an embodiment, the ODT disintegrates in less than 30 seconds from coming into contact with saliva. In an embodiment, the ODT disintegrates in 3-10 seconds. In an embodiment, there is provided the use of a 5-MeO-DMT benzoate ODT in a method of treatment. In an embodiment, there is provided the use of a 5-MeO-DMT benzoate ODT in the method of manufacture of a medicament for a therapeutic application.
Nasal
In an embodiment, there is provided a nasal formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a spray-dried nasal formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a spray- dried amorphous particulate powder formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a spray-dried amorphous particulate powder formulation of 5-MeO-DMT benzoate, wherein the formulation has been co-sprayed with hydroxypropyl methylcellulose (HPMC). In an embodiment, the nasal formulation has a median particle size of 10 to 100 micron, 20 to 90 micron, 30 to 80 micron, 40 to 70 micron, 30 to 60 micron or 40 to 50 micron. In an embodiment, the nasal formulation has a median particle size of 20 to 40 micron. In an embodiment, there is provided the use of a nasal formulation of 5-MeO-DMT benzoate in a method of treatment. In an embodiment, there is provided the use of a nasal formulation of 5-MeO-DMT benzoate in the method of manufacture of a medicament for a therapeutic application.
Transdermal
In an embodiment, there is provided a microneedle array for use in administration of the 5-MeO-DMT, wherein said array comprises a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable composition. In an embodiment, there is provided a microneedle array for use in administration of the 5-MeO-DMT, wherein said array comprises a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable hydrogel forming polymer composition. Any hydrogel polymer composition which can penetrate the stratum corneum of skin and which swells in the presence of liquid may be used. In an embodiment, the microneedles are fabricated from one or more hydrogel-forming polymers containing one or more hydrophilic functional groups. Examples of suitable polymers include, but are not necessarily limited to, polyvinylalcohol), amylopectin, carboxymethylcellulose (CMC)chitosan, poly(hydroxyethylmethacrylate) (polyHEMA), poly(acrylic acid), and poly(caprolactone), or a Gantrez ® -type polymer. Gantrez ® -type polymers include poly(methylvinylether/maleic acid), esters thereof and similar, related, polymers (eg poly(methyl/vinyl ether/maleic anhydride).
In a particular embodiment of the invention, the hydrogel-forming polymer is a Gantrez ® -type polymer such as poly(methyl/vinyl ether/maleic acid) (PMVEMA), an ester thereof or poly(methyl/vinyl ether/maleic anhydride) (PMVEMAH). Crosslinking of polymers may be used to further vary the strength and swelling characteristics of microneedles as well as the release characteristics of the microneedles. For example, a lightly-crosslinked hydrogel microneedle could rapidly deliver a drug bolus where one dose only is required e.g. for vaccine delivery. Optionally, a moderately-crosslinked hydrogel microneedle could be used to allow prolonged drug delivery, thus facilitating a constant drug plasma level. Optionally moderately-crosslinked hydrogel microneedles could keep puncture holes in the SC open. Indeed, moderately-crosslinked hydrogel microneedles might optionally widen the puncture holes as a result of absorption of moisture from tissue, and swelling of the microneedles.
The polymer composition of the microneedles and/or the base element may be cross-linked using any suitable technique known in the art. The crosslinking may be physical or chemical or a combination of both. Suitable crosslinking agents include polyhydric alcohols (eg glycerol, propylene glycol (poly(ethylene glycol) or a polyamino compound which can form amides with reactive groups of a polymer. In one embodiment, of the invention, the hydrogel-forming polymer is a Gantrez ® type polymer cross-linked using a polyhydric alcohol.
The microneedles of the microneedle arrays of the invention may be of any size and shape such that they can penetrate the stratum corneum of mammalian skin without breaking upon their insertion into the skin. In one embodiment, the microneedles of the microneedle arrays of the invention are 1 - 3000 pm in height. In one embodiment, the microneedles have a width (or, in the case of microneedles with substantially circular cross sections, a diameter) of 50 - 500 pm. The base element and microneedles may be comprised of the same or different materials. Typically the base element will be composed of the same polymer composition as the microneedles. The mechanical strength and rate of swelling of the microneedles of the microneedle arrays of the invention will be determined by a number of factors including the shape of the microneedles and the polymer(s) of which the microneedles are composed.
In an embodiment, there is provided a transdermal delivery device comprising a microneedle array as previously or subsequently described. In such transdermal delivery devices, the 5-MeO-DMT (optionally the benzoate salt) may be comprised within a reservoir or matrix with which the microneedle array is in communication. In use, on insertion of the microneedle array into skin, the 5-MeO-DMT (optionally the benzoate salt) moves from the reservoir or matrix through the microneedles to the skin. Additionally or alternatively, the 5-MeO-DMT (optionally the benzoate salt) may be comprised within the polymer composition of the microneedle array. This has the distinct advantage over conventional microneedle arrays in which drugs are delivered via a channel in the microneedle that, on insertion into the skin, drug delivery may be initiated almost immediately. In particular embodiments, 5-MeO-DMT (optionally the benzoate salt) can be chemically bonded to the polymer(s) making up the microneedles and/or base elements. In this case, the 5-MeO-DMT (optionally the benzoate salt) can be released upon insertion into the skin by; dissolution of the microneedles, hydrolysis, enzymatic or spontaneous non-catalysed breakage of the bonds holding it to the polymer(s). The rate of drug release can thus be determined by the rate of reaction/bond breakage.
In embodiments of the transdermal delivery device of the invention, movement of 5-MeO-DMT (optionally the benzoate salt) from the microneedle array into the skin may occur passively. Alternatively, movement may be controlled externally, for example iontophoretically. In an embodiment, there is provided an iontophoretic device comprising a microneedle array as previously or subsequently described. In an embodiment, there is provided a method of delivering 5-MeO-DMT (optionally the benzoate salt) through or into the skin comprising providing a microneedle array or a transdermal therapeutic device, either of which may be as previously or subsequently described, wherein the microneedle array or transdermal therapeutic device comprises 5- MeO-DMT (optionally the benzoate salt), applying the microneedle array to the skin such that the microneedles protrude through or into the stratum corneum, allowing the microneedles to swell, allowing the 5-MeO-DMT (optionally the benzoate salt) to flow through the microprotusions into the skin. Transdermal delivery devices can be affixed to the skin or other tissue to deliver 5-MeO-DMT (optionally the benzoate salt) continuously or intermittently, for example for durations ranging from a few seconds to several hours or days. Arrays of microneedles having different characteristics from each other, for example having different shapes, polymer compositions, crosslinkers or degrees of crosslinking, thus enabling a single microneedle array to have regions which can deliver drugs at different rates. This would enable, for example, a rapid bolus to be delivered to a patient on positioning of the microneedle array followed by a slower sustained release of the same active agent. Indeed, the microneedle arrays of the invention may be used to deliver more than one active agent from the same transdermal therapeutic device. For example, a first active agent could be comprised within the polymer of which the microneedles are composed with a second active agent stored in a reservoir. On positioning on the skin and puncturing of the stratum corneum, the microneedles will swell and the active agent will be released from the microneedles. Subsequently, the second active agent may be released from the reservoir and enter the skin via the microneedles.
Drug contained in the microneedles themselves will be rapidly released upon swelling, initially as a burst release due to drug at the surface of the microneedles. The subsequent extent of release will be determined by crosslink density and the physicochemical properties of the drug. Release of drug from the drug reservoir will occur more slowly at first as a result of the time required to swell the microneedles up as far as the drug reservoir, subsequent partitioning of the drug into the swollen microneedles and diffusion of the drug through the swollen matrix. The microarrays may thus be adapted to deliver two active agents in succession, with the composition adapted, e.g. by crosslinking of the composition of the microneedles, to vary delivery times of one or both active agents.
In an embodiment, there is provided a microneedle array for use in the administration of 5-MeO-DMT (optionally the benzoate salt), wherein said array comprises a plurality of microneedles composed of a swellable polymer composition which in its dry state is hard and brittle to penetrate the stratum corneum of a patients skin, wherein the microneedles are fabricated from at least one polymer selected from poly(methylvinylether/maleic acid), esters thereof and poly (methyl/vinyl ether/maleic anhydride), wherein the polymer is a cross-linked polymer, and using a cross-linker at a polymer-crosslinker ratio of 2:1. In an embodiment, there is provided a transdermal delivery device capable of the administration of two different active agents with different release profiles. The first active agent is delivered rapidly over less than 5, less than 10 or less than 15 minutes. The second active agent is delivered only after the rapid delivery of the first active agent.
In an embodiment, the first active agent is, for example, coated on the outer service of each of a plurality of microneedles whilst the second active agent is, for example, localised on an inner layer of each of a plurality of microneedles. In an embodiment, the outer surface of each microneedle is dissolvable. In an embodiment, the inner layer(s) of each microneedle comprise a swellable polymer mix, such as a hydrogel. In an embodiment, the first active agent is coated on and/or localised on an inner layer of the tip of each microneedle. In an embodiment, the second active agent is localised on an inner layer of the remainder of each microneedle. In an embodiment, the tip of each microneedle dissolves rapidly upon application to a patient/activation to release the first active agent rapidly. In an embodiment, the second active agent is released following the rapid release of the first.
In an embodiment, there is provided a transdermal delivery device comprising a plurality of a first type of microneedle and a plurality of a second type of microneedle. In an embodiment, the first type of microneedle is a rapidly dissolvable microneedle. In an embodiment, the outer surface and/or the inner layer(s) of each of the first type of microneedle are coated with/have localised therein a first active agent. In an embodiment, the second type of microneedle is a microneedle comprising a swellable polymer composition. In an embodiment, the second type of microneedle comprising a second active agent.
Example 41: HPLC Method
An isocratic RP-HPLC method was also developed for assay of delivered-dose and the method parameters are listed in the Table below.
The reversed phase High-Performance Liquid Chromatography (RP-HPLC) method forthe quantitative determination of assay and chemical purity of 5-MeO-DMT has been verified using the development of the 5-MeO-DMT benzoate drug substance. The method has been verified in terms of system suitability, specificity, limit of quantitation, linearity, accuracy and precision over a quantification range of 0.00005 to 0.13mg/ml 5-MeO-DMT benzoate. A summary of the verification results can be found in the Table below.
The isocratic RP-HPLC method was also verified, and a summary of the results are listed in the Table below.
Example 42: Effect of5-MeO-DMT benzoate on LPS-induced cytokine induction in human whole blood cultures
Experimental Design:
The study had 8 experimental groups and 1 control group with n=5 per group. Human whole blood (healthy donors between the age of 18 and 65, n=5, 9 treatments per sample) was mixed 1:1 with RPMI 1640 media containing 1% penicillin/streptomycin antibiotic before addition to the culture wells. 5-MeO-DMT benzoate was made up to a stock solution of 40 mg/ml in dHzO, before dilution to a lOOx concentrated solution (10,000pM). This lOOx solution was then diluted 1 in 100 in the well (5pl in 500pl) for a final concentration of 100pM. 100pM 5-MeO-DMT benzoate was added to the whole blood culture either 120 minutes, 60 minutes or 0 minutes prior to 2 ng/ml LPS treatment, and 30 minutes, 60 minutes or 120 minutes post 2 ng/ml LPS treatment. dHzO was used as the vehicle for both 5-MeO- DMT benzoate and LPS. 5-MeO-DMT Benzoate was also administered 120 minutes prior to vehicle treatment. LPS was diluted down to a 200ng/ml solution from a stock solution of 5mg/ml in dHzO before 1 in 100 dilution in the wells (5pl in 500pl) for a final concentration of 2 ng/ml.
Following treatment, whole blood was collected into 1.5ml Eppendorf tubes before centrifugation at 2000 x g for 20 minutes. Whole blood supernatant was then collected and analysed using the Meso Scale Discovery system for the quantification of the levels of cytokines TNF-a, IL-lfJ, IL-6 and IL-10 using a customised 4-panel V-plex pro- inflammatory panel kit (MSD, V-Plex Cat No.K15049D). 50pl of whole blood supernatant was added in duplicate to the wells of the MSD plate (vehicle-treated samples diluted 1:4, LPS-treated samples diluted 1:100). Whole blood cultures were maintained under sterile conditions in a cell culture incubator at 5% CO2 and a temperature of 37°C.
Drug preparation:
Lipopolysaccharide serotype O111:B4 from E. coli. was purchased from Sigma-Aldrich (Cat. No. L2630) prepared in dHzO at a concentration of 200 ng/ml and diluted 1:100 in the culture wells for a final concentration of 2 ng/ml (5pl in 500pl). 5-MeO-DMT benzoate salt was obtained from Beckley Psytech (450mg) and prepared in dHzO at a stock concentration of 40mg/ml (115mM). The stock solution was diluted to 10,000pM in dHzO before 1:100 dilution in the culture wells for a final concentration of 100 pM (5pl in 500pl).
Sample collection and analysis:
Following treatment, whole blood was collected into 1.5ml Eppendorf tubes before centrifugation at 2000 x g for 20 minutes. Whole blood supernatant was then collected and analysed using the Meso Scale Discovery system for the quantification of the levels of cytokines TNF-a, IL-lfJ, IL-6 and IL-10 using a customised 4-panel V-plex pro- inflammatory panel kit (MSD, V-Plex Cat No.K15049D). 50pl of whole blood supernatant was added in duplicate to the wells of the MSD plate (vehicle-treated samples diluted 1:4, LPS-treated samples diluted 1:100).
Analysis:
One-way analysis of variance (ANOVA) was used to detect statistical significance. The Fisher least significant difference (LSD) test was employed for post hoc analysis. Probability values of P<0.05 are considered statistically significant. Statistical analyses were performed using GraphPad Prism V8.
Summary data:
Summary data tables representing whole blood cytokine levels. Data presented as pg/ml.
1. TN F-a expression with treatment of 5-MeO-DMT benzoate pre- and post-LPS:
One-way ANOVA showed a main effect of treatment P<0.0001 on TNF-a release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. **** Significant difference compared to vehicle. Results seen in Figure 118.
2. IL-lfJ expression with treatment of 5-MeO-DMT benzoate pre- and post-LPS: One-way ANOVA showed a main effect of treatment P=0.0049 on IL-lfJ release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. *** Significant difference compared to vehicle. + Significant difference compared to LPS 2 ng/ml. ++ Significant difference compared to LPS 2 ng/ml. Results seen in Figure 119.
3. IL-6 expression with treatment of 5-MeO-DMT benzoate pre- and post-LPS:
One-way ANOVA showed a main effect of treatment P<0.0001on IL-6 release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. ** Significant difference compared to vehicle. + Significant difference compared to LPS 2 ng/ml. ++ Significant difference compared to LPS 2 ng/ml. Results seen in Figure 120.
4. IL- 10 expression with treatment of 5-MeO-DMT benzoate pre- and post-LPS:
One-way ANOVA showed no effect of treatment P=0.2131 on IL- 10 release. Post-hoc Fishers LSD was used for multiple comparisons. Data presented as Mean ± SEM. n=5. Results can be seen in Figure 121.
Result
Treatment of human whole blood with 5-MeO-DMT benzoate at 60 minutes and 120 minutes post-LPS treatment produced a significant reduction in LPS-induced IL-lfJ expression.
Example 43: Anti-inflammatory embodiments
Interleukin 1 beta (IL-1P) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. Increased production of IL-lfJ causes a number of different autoinflammatory syndromes, most notably the monogenic conditions referred to as Cryopyrin-Associated Periodic Syndromes (CAPS), due to mutations in the inflammasome receptor NLRP3 which triggers processing of IL-1B. The presence of IL-lfJ has been also found in patients with multiple sclerosis (a chronic autoimmune disease of the central nervous system). Treatment of multiple sclerosis with glatiramer acetate or natalizumab has been shown to reduce the presence of IL-lfJ.
Over-expression of IL-lfJ caused by inflammasome may result in carcinogenesis. Some data suggests that NLRP3 inflammasome polymorphisms is connected to malignancies such as colon cancer and melanoma. It has been reported that IL-lfJ secretion was elevated in the lung adenocarcinoma cell line A549. It has also been shown that IL-ip, together with IL-8, plays an important role in chemoresistance of malignant pleural mesothelioma by inducing expression of transmembrane transporters. It has also been shown that inhibition of inflammasome and IL-ip expression decreased the development of cancer cells in melanoma. It has been shown that the IL-1 family plays an important role in inflammation in many degenerative diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. Significantly increased protein level of IL-lfJ has been found in the vitreous of diabetic retinopathy patients.
IL-lfJ has also been linked to depression, as described in a 2017 review by Farooq et al (Farooq RK, Asghar K, Kanwal S, Zulqernain A. Role of inflammatory cytokines in depression: Focus on interleukin-lfJ. Biomed Rep. 2017;6(l):15- 20. doi:10.3892/br.2016.807). Acutely depressed and unmedicated patients have been found to have higher concentrations of the pro-inflammatory IL-lfJ in their cerebral spinal fluid (CSF). There remains a need for methods of, and/or pharmaceutical compositions to reduce the expression of IL-lfJ.
Herein disclosed, is 5-MeO-DMT benzoate for use in the treatment of a disorder associated with the expression of the pro-inflammatory cytokine IL-lfJ. Herein disclosed are methods of treatment utilising and compositions comprising 5-MeO-DMT benzoate. In an embodiment, there is provided 5-MeO-DMT benzoate for use in a method of treatment, wherein administration of 5-MeO-DMT benzoate to a patient in need thereof reduces the expression of the pro-inflammatory cytokine IL-lfJ. 5-methoxy-N,N-dimethyltryptamine is a pharmacologically active compound of the tryptamine class and has the chemical formula:
5-MeO-DMT is a psychoactive/psychedelic substance found in nature and is believed to act mainly through serotonin receptors. It is also believed to have a high affinity for the 5-HT2 and 5-HT1A subtypes, and/or inhibits monoamine reuptake. 5-methoxy-N,N-dimethyltryptamine chloride (hereafter 5-MeO-DMT chloride or the chloride salt) is known and is the most commonly used salt form of 5-MeO-DMT, and is the resultant hydrochloride adduct of the free base shown above (i.e. this can be drawn where the freebase is protonated and the counter ion is a chloride anion). 5-methoxy-N,N-dimethyltryptamine benzoate (hereafter 5-MeO-DMT benzoate or the benzoate salt) is the resultant benzoic acid adduct of the free base, i.e. this can be drawn where the free base is protonated and where the counter ion is a benzoate anion:
Disclosed herein, the benzoate salt of 5-MeO-DMT has improved characteristics over the hydrochloride salt, including reduced mucosal irritation, increased epithelial permeability and increased stability. 5-MeO-DMT benzoate is a white to off white solid powder, molecular weight 340.40 g/mol, soluble in water at >50mg/ml with a pH of 7-8 at 50mg/ml and a pKa of 9.71.
Disclosed herein, the benzoate salt of 5-MeO-DMT has been found to reduce the expression of I L-lfJ, and so is useful in the treatment of a disorder associated with the expression of the pro-inflammatory cytokine IL-lfJ; e.g. may be used to reduce the expression of pro-inflammatory cytokine IL-lfJ. As such, the benzoate salt having the improved characteristics over the commercially available hydrochloride salt together with pro-inflammatory cytokine IL-lfJ activity disclosed herein, offers improved patient treatment outcomes.
In an aspect, there is provided an anti-inflammatory composition comprising 5-MeO-DMT benzoate. Advantageously, 5-MeO-DMT benzoate, and compositions comprising 5-MeO-DMT benzoate, reduce the levels of IL-ip expression.
In an embodiment, there is provided 5-MeO-DMT benzoate for use in a method of treatment, wherein administration of 5-MeO-DMT benzoate to a patient in need thereof reduces the expression of the pro- inflammatory cytokine IL-lfJ. In an embodiment, the method of treatment is a method of treatment of any condition benefiting from the reduction of IL-lfJ. In an embodiment, the method of treatment is a method of treatment of inflammation. In an embodiment, the inflammation is chronic. In an embodiment, the inflammation is acute. In an embodiment, the method of treatment is a method of treatment of multiple sclerosis. In an embodiment, the method of treatment is a method of treatment of post viral fatigue (PVF), such as long COVID. In an embodiment, the method of treatment is a method of treatment of age-related macular degeneration, osteomyelitis, rheumatoid arthritis, diabetic retinopathy, retinitis pigmentosa or Cryopyrin-Associated Periodic Syndromes (CAPS). In an embodiment, the method of treatment is a method of treatment of acute, or chronic pain, including neuropathic pain. In an embodiment, the method of treatment is a method of treatment of pain associated with or caused by one or more of:
Headache;
Trigeminal autonomic cephalalgia (TAC) (such as cluster headache, paroxysmal hemicranias, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) or long-lasting autonomic symptoms with hemicranias (LASH); or migraine.
In an embodiment, the method of treatment is a method of treatment of one or more of:
Headache;
Trigeminal autonomic cephalalgia (TAC) (such as cluster headache, paroxysmal hemicranias, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) or long-lasting autonomic symptoms with hemicranias (LASH); or migraine.
In an embodiment, the method of treatment is a method of prophylactic treatment. In an embodiment, the method of treatment is a method of prophylactic treatment of preventing the development of chronic migraine. In an embodiment, the method of treatment is a method of prophylactic treatment of pain associated with or caused by one or more conditions. In an embodiment, the method of treatment is a method of treatment of fibromyalgia. In an embodiment, the method of treatment is a method of treatment of, or a method of preventing the development of, traumatic brain injury. In an embodiment, the method of treatment is a method of treatment wherein the 5- MeO-DMT benzoate is used as part of a rehabilitation programme. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO-DMT benzoate is used as part of a rehabilitation programme for traumatic brain injury. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO- DMT benzoate is used to lessen the permanent sequelae from a traumatic brain injury. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO-DMT benzoate is used to lessen the neurologic or psychiatric deficit after a traumatic brain injury and/or cerebral ischemia related to a stroke, or global brain hypoxia, or an intracranial or epidural bleeding. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO-DMT benzoate is used to lessen the neurologic or psychiatric deficit after an injury. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO-DMT benzoate is used to lessen the neurologic or psychiatric deficit after a brain injury. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO-DMT benzoate is used to lessen the neurologic or psychiatric deficit associated with a disease or condition. In an embodiment, the method of treatment is a method of treatment wherein the 5-MeO-DMT benzoate is used to lessen the neurologic or psychiatric deficit associated with a degenerative disease or disorder. In an embodiment, the method of treatment is a method of treatment of a psychological/psychiatric disorder.
In an embodiment, the method of treatment is a method of treatment of one or more of:
Anxiety disorders; Substance use disorders; Post-traumatic stress disorder (PTSD); Eating disorders; Obsessive- compulsive disorders; Body dysmorphic disorders; Mood disorders; Sleep disorders; Personality disorders; Psychotic disorders; Impulse control disorders; Dissociative disorders; Cognitive disorders; or Developmental disorders.
In an embodiment, the mood disorder is depression. In an embodiment, the mood disorder is major depressive disorder. In an embodiment, the mood disorder is treatment-resistant depression. In an embodiment, the method of treatment is a method of treatment of bipolar disorder. In an embodiment, the method of treatment is a method of treatment of alcohol abuse/addiction. In an embodiment, the method of treatment is a method of treatment of drug abuse/addiction. In an embodiment, the method of treatment is a method of treatment of nicotine abuse/addiction. In an embodiment, the method of treatment is a method of treatment of schizophrenia. In an embodiment, the method of treatment is a method of treatment of autism. In an embodiment, the method of treatment is a method of treatment of childhood trauma. In an embodiment, the method of treatment is a method of treatment of phobias. In an embodiment, the method of treatment is a method of treatment of anxiety, generalized anxiety and/or social anxiety. In an embodiment, the method of treatment is a method of treatment of cancer. In an embodiment, the method of treatment is a method of treatment of colon cancer, melanoma or lung cancer. In an embodiment, the method of treatment is a method of treating malignant pleural mesothelioma. In an embodiment, the method of treatment is a method of treatment of a degenerative condition such as Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis (ALS). In an embodiment, the method of treatment is a method oftreatment of a seizure disorder, such as epilepsy. In an embodiment, the method of treatment is a method of treatment wherein the method of treatment comprises the administration of a sub-perceptual dose of 5-MeO- DMT benzoate. In an embodiment, the method of treatment comprises the administration of a crystalline form of 5-MeO-DMT benzoate as described previously or subsequently. In an embodiment, the method of treatment comprises the administration of 5-MeO-DMT in combination with a second active agent. In an embodiment, the second active agent is one or more of any of the second active agents/drugs described previously or subsequently. In an embodiment, the method of treatment is a method of treatment of one or more of any of the conditions/diseases described previously or subsequently.
In an embodiment, there is provided an anti-inflammatory pharmaceutical composition comprising 5-MeO-DMT. In an embodiment, the composition comprises 5-MeO-DMT benzoate, or a crystalline form thereof. In an embodiment, the composition comprises 5-MeO-DMT HCI, or a crystalline form thereof. In an embodiment, there is provided the use of said pharmaceutical composition in a method of treatment of any of the aforementioned or subsequently mentioned conditions.
Example 44: Prescription Digital Therapeutics (PDT)
Herein provided are methods of treatment utilising and compositions comprising 5-MeO-DMT benzoate in combination with a prescription digital therapeutic (PDT).
In an aspect, there is provided a prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises: administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof; monitoring the interaction of the patient with one or more components of the PDT via one or more electronic devices or inputs linked thereto; assessing the interaction of the patient with the one or more components of the PDT; determining the response of the patient to the administered dose of the 5-MeO-DMT benzoate salt based on the assessment of the interaction of the patient with the one or more components of the PDT; and recommending a dose of the 5-MeO-DMT benzoate salt for further administration, or a cessation of further doses of the 5-MeO-DMT benzoate salt.
Advantageously, 5-MeO-DMT benzoate is administered together with the PDT. In an embodiment, the method comprises the detection of relapse. In an embodiment, the method comprises recommending a dose of the 5-MeO- DMT benzoate to enhance the patient response to the treatment.
In an embodiment, the one or more components of the PDT comprise: guided meditation; breathing exercises; neuro/bio-feedback exercises; journaling; surveys/questionnaires; video and/or audio content; remote contact with one or more healthcare professionals (HCPs) and/or one or more peers who have experienced 5-MeO-DMT benzoate treatment (hereafter 'peers'); therapy tasks, such as the Values Card Sort Task; remote cognitive behavioural therapy (CBT);
Al chat tools; and automated reminders and/or alerts.
A prescription digital therapeutic (PDT) is a prescription-only software that delivers evidence-based therapeutic intervention(s) to prevent, manage or treat a medical disorder or disease. Herein disclosed is the use of PDT in connection with treatment of a patient with 5-MeO-DMT (i.e. a potent psychoactive/psychedelic substance) to assist, improve and/or optimize the patient treatment outcomes, which can be altered positively (or negatively) depending on how the patient is managed.
As such, patient preparation prior to treatment with 5-MeO-DMT is believe to be important for optimal experience and outcomes. That is, the 5-MeO-DMT experience is visually and experientially all encompassing, with limited connection to the physical environment. The intensity of the experience with 5-MeO-DMT is such that conscious control or direction of the experience is not possible, therefore there is perhaps a greater need for pre-therapy preparation to enter the experience in the right sub-conscious state/mindset. Administration of 5-MeO-DMT is believed to generate a neuroplastic effect such that delivery of psychotherapy in the weeks after treatment generates a greater impact on outcomes. Long term, identifying the return of symptoms and the need for retreatment or therapy may be important for delivering sustained recovery.
The methods are designed to be delivered prior to and after administration of 5-MeO-DMT, for psychological/psychiatric conditions via a digital platform and uses actively and passively entered data to support preparation, post-treatment integration, and ongoing therapy to enhance and sustain patient response to treatment.
The methods are also useful in screening potential candidates prior to treatment with 5-MeO-DMT for likelihood and/or type of treatment response. A combination of active and passive data is used to generate a response profile that indicates whether treatment with 5-MeO-DMT will be safe and effective. Based on the identified response profile of the individual, the method may provide a clinician with a recommendation on the optimal treatment protocol (therapy, drug, dose etc), and determines any settings for automated preparation, in-experience setting and post-treatment integration. The methods support integration through automated content, therapy, and connecting individuals to therapists remotely, and to others who have also experienced 5-MeO-DMT therapy. In an embodiment, the method additionally comprises the interaction of the patient with one or more components of the PDT occurs prior to administration of the dose of the 5-MeO-DMT benzoate salt. In an embodiment, the method additionally comprises the interaction of the patient with one or more components of the PDT occurs prior to administration of the dose of the 5-MeO-DMT benzoate salt, wherein administration of the dose of the 5-MeO-DMT benzoate only occurs if the interaction of the patient with one or more components of the PDT indicates the patient is likely to respond favourably to such administration.
Favourable (or disfavourable) response may for example be determined in an appropriate manner, e.g. as suggested by one or more of:
Favourable response may for example determined in an appropriate manner, e.g. as suggested by one or more of: lower scores on symptom severity at the start of treatment could indicate good response, i.e. fewer negatively valenced words, lower scores on depression surveys; engagement with preparation: users who open the PDT/app and engage on a daily basis prior to 5-MeO-DMT administration may be more likely to respond well; lack of physical co-morbidities: e.g. user tend to respond better to CBT, and so show a similar profile with 5-MeO- DMT; social engagement/support: passive measures of social interaction (number of text messages, calls, nearby Bluetooth connections) as associated with better outcomes post 5-MeO-DMT treatment; cognitive function/flexibility: users who have faster response times, inhibition (as measured by speed and pattern of tapping on the smartphone screen) and other measures of executive function may demonstrate increased cognitive flexibility post 5-MeO-DMT and therefore the impact of 5-MeO-DMT and/or therapy is believed to be greater, leading to better outcomes
In an embodiment, an interaction with Al chat tool wherein the patient responds negatively to a series of questions indicates that they are unlikely to respond favourably to 5-MeO-DMT benzoate administration. In an embodiment, lower scores on symptom severity at the start of treatment indicates good response (i.e. fewer negatively valenced words, lower scores on depression surveys). In an embodiment, higher engagement by the patient with the one or more components of the PDT indicates that they are likely to respond favourably to 5-MeO-DMT benzoate administration. In an embodiment, declining levels of engagement by the patient with the one or more components of the PDT during treatment may indicate relapse. In an embodiment, low levels of engagement by the patient with the one or more components of the PDT prior to treatment may indicate that they are unlikely to respond to favourably to such treatment. In an embodiment, a low measure of social engagement/support prior to or during treatment may indicate that a patient is unlikely to respond favourably to treatment. In an embodiment, a low measure of social engagement/support is determined by measures of social interaction (number of text messages, calls, nearby Bluetooth™ connections). In an embodiment, the speed of a patient interaction with the one or more components of the PDT may indicate whether or not the patient is likely to respond favourably to treatment with 5- MeO-DMT benzoate and/or respond favourably to continued treatment with 5-MeO-DMT benzoate. In an embodiment, a slow speed of patient interaction may indicate the patient is less likely to respond favourably. In an embodiment, a low number of taps on a phone screen per minute during interaction with the one or more components of the PDT may indicate the patient is less likely to respond favourably. In an embodiment, a high number of taps on a phone screen per minute during interaction with the one or more components of the PDT may indicate the patient is more likely to respond favourably. In an embodiment, a fast response/speed of patient interaction may indicate the patient is more likely to respond favourably. In an embodiment, the patient interacts with one or more components of the PDT via a dedicated application (app) present, or hosted, on one or more electronic devices.
In an embodiment, the app records data regarding the interaction of the patient with one or more of the: guided meditation; breathing exercises; journaling; surveys/questionnaires; video and/or audio content; remote HCPs and/or one or more peers who have experienced 5-MeO-DMT benzoate treatment (hereafter 'peers'); therapy tasks; remote CBT; Al chat tools; and automated reminders and/or alerts and wherein the data is for use in determining the response of the patient to the administered dose of the 5-MeO- DMT benzoate salt, and/or for recommending a dose of the 5-MeO-DMT benzoate salt for further administration, or a cessation of further doses of the 5-MeO-DMT benzoate salt.
In an embodiment, the app records data regarding the interaction of the patient with one or more of: human electronic device interaction patterns (e.g. screen touches); patient movement (e.g. accelerometer and/or gyroscope data and/or GPS location data and/or Wi-Fi network interaction data); patient physiology (e.g. heart rate and/or respiratory rate and/or galvanic skin response and/or blood pressure and/or temperature data and/or EEG data); patient eye movement and blinking patterns; patient facial movement patterns; patient sleep patterns (e.g. frequency and/or duration and/or quality, as derived from electronic device usage patterns, actigraphy etc.); patient communication patterns (e.g. messaging data and/or voice call data and/or voice over internet protocol [VoIP] data and/or contacts communicated with data and/or duration of inbound and outbound call data and/or instant messaging data); and/or app usage data (e.g. number of app opens and/or duration of app usage and/or type of app usage).
In an embodiment, determining the response of the patient and/or recommending a dose of the 5-MeO-DMT benzoate salt is done remotely by, or with the input from, one or more HCPs. In an embodiment, determining the response of the patient and/or recommending a dose of the 5-MeO-DMT benzoate salt is done remotely by, or with the input from, one or more algorithms. In an embodiment, determining the response of the patient and/or recommending a dose of the 5-MeO-DMT benzoate salt is done remotely by, or with the input from, one or more HCPs and one or more algorithms. In an embodiment, determining the response of the patient includes determining whether or not the patient is currently, or in danger of, relapsing.
In an embodiment, if it is determined that there is no, or little, beneficial response of the patient, then: a treatment change is initiated to the dose of the 5-MeO-DMT benzoate salt; and/or a treatment change is initiated to the one or more components of the PDT. In an embodiment, the treatment change is initiated by, or with the input from, one or more algorithms. In an embodiment, the treatment change is initiated by, or with the input from, one or more HCPs. In an embodiment, the treatment change is initiated by, or with the input from, one or more HCPs and one or more algorithms.
In an embodiment, the treatment change comprises a change in one or more of: dose of the 5-MeO-DMT benzoate salt; frequency of administration of the 5-MeO-DMT benzoate salt; form of administration of the 5-MeO-DMT benzoate salt; and components of the PDT.
In an embodiment, the change in the one or more components of the PDT is selected from a change in one or more of: guided meditation; breathing exercises; neuro/bio-feedback exercises; journaling; surveys/questionnaires; video and/or audio content; remote contact with one or more HCPs and/or one or more peers who have experienced 5- MeO-DMT benzoate treatment (hereafter 'peers'); therapy tasks, such as the Values Card Sort Task; remote cognitive behavioural therapy (CBT); Al chat tools; and automated reminders and/or alerts.
In an embodiment, the one or more electronic devices are selected from: smart device; smartphone; smartwatch; smart glasses; smart ring; smart patch; home hub smart device (e.g. Amazon Alexa™); fitness tracker; personal computer; tablet (e.g. iPad™); and/or EEG monitor.
In an embodiment, the PDT itself initiates a change to the PDT based on the data gathered by one or more electronic devices. In an embodiment, the one or more electronic devices records and transmits data associated with the patient and/or their interactions with one or more components of the PDT to a third party, optionally the third party is one or more HCPs. In an embodiment, the data is transmitted via a secure backend service. In an embodiment, the data is encrypted prior to transmission. In an embodiment, based on the transmitted data, the third party who is optionally one or more HCPs, initiates a treatment change to the dose of the 5-MeO-DMT benzoate salt, and/or a treatment change to the one or more components of the PDT.
In an embodiment, the dosage amount of the dose of the 5-MeO-DMT benzoate salt is 1 to lOOmg. In an embodiment, the dosage amount of the dose of the 5-MeO-DMT benzoate salt is 0.1 to lOOOmg. In an embodiment, the 5-MeO-DMT benzoate salt is formulated in an intranasal composition at a concentration of 70-140mg/ml and wherein the dose of the 5-MeO-DMT benzoate salt is administered to the patient via an intranasal route. In an embodiment, the 5-MeO-DMT benzoate salt is administered to the patient in the presence of a HCP in a dedicated treatment room, and optionally wherein the patient is sat down.
In an embodiment, the method of treatment is for the treatment of any one of: conditions caused by dysfunctions of the central nervous system; conditions caused by dysfunctions of the peripheral nervous system; conditions benefiting from sleep regulation (such as insomnia); conditions benefiting from analgesics (such as chronic pain); migraines; trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)); conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia); conditions benefiting from anti-inflammatory treatment; depression; treatment-resistant depression; anxiety; substance use disorder; addictive disorder; gambling disorder; eating disorders; mood disorders, such as PTSD; obsessive-compulsive disorders; and body dysmorphic disorders.
In an embodiment, the method of treatment is for the treatment of treatment-resistant depression.
In an embodiment, the method comprises: administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof; wherein the dose is administered intranasally in a dosage amount of 1 to 50mg; monitoring the interaction of the patient with one or more components of the PDT via one or more electronic devices or inputs linked thereto; wherein the electronic device is a smart phone and the one or more components comprise, or consists of, remote CBT, guided meditation, breathing exercises, therapy tasks, surveys/questionnaires, remote contact with HCPs and/or one or more peers who have experienced 5-MeO-DMT benzoate treatment (hereafter 'peers') and journals; assessing the interaction of the patient with the one or more components of the PDT; determining the response of the patient to the administered dose of the 5-MeO-DMT benzoate salt based on the assessment of the interaction of the patient with the one or more components of the PDT; and recommending a dose of the 5-MeO-DMT benzoate salt for further administration, or a cessation of further doses of the 5-MeO-DMT benzoate salt, wherein determining the response of the patient and/or recommending a dose of the 5-MeO-DMT benzoate salt is done remotely by, or with the input from, one or more HCPs and/or one or more algorithms; wherein if it is determined that there is no, or little, beneficial response of the patient, then a treatment change is initiated to the dose of the 5-MeO-DMT benzoate salt, and/or a treatment change is initiated to the one or more components of the PDT; wherein optionally, the treatment change comprises an increase in one or more of: the dosage amount of the 5-MeO-DMT benzoate salt; frequency of administration of the 5-MeO-DMT benzoate salt; and frequency of remote therapy (such as CBT).
In an embodiment, the 5-MeO-DMT benzoate salt is crystalline and characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A.
In an embodiment, there is provided a prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof, wherein the method of treatment is for the treatment of any one of: conditions caused by dysfunctions of the central nervous system; conditions caused by dysfunctions of the peripheral nervous system; conditions benefiting from sleep regulation (such as insomnia); conditions benefiting from analgesics (such as chronic pain); migraines; trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)); conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia); conditions benefiting from anti-inflammatory treatment; depression; treatment-resistant depression; anxiety; substance use disorder; addictive disorder; gambling disorder; eating disorders; mood disorders, such as PTSD; obsessive-compulsive disorders; or body dysmorphic disorders.
In an embodiment, there is provided a prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof, wherein the method of treatment is for the treatment of treatment-resistant depression.
In an embodiment, there is provided the use of 5-MeO-DMT, optionally the benzoate salt, in a method of treatment, wherein the method comprises administering 5-MeO-DMT, optionally the benzoate salt, to a patient in need thereof wherein the patient has, prior to administration of the 5-MeO-DMT, taken part in a virtual reality (VR) experience designed to prepare the patient for psychedelic therapy.
In an embodiment, the method of treatment further comprises additional VR experiences to complement the psychedelic therapy.
In an embodiment, there is provided the use of 5-MeO-DMT, optionally the benzoate salt, in a method of treatmentresistant depression treatment, wherein the method comprises administering 5-MeO-DMT, optionally the benzoate salt, to a patient in need thereof wherein the patient has, prior to administration of the 5-MeO-DMT, taken part in a virtual reality (VR) experience designed to prepare the patient for psychedelic therapy.
In an embodiment, there is provided a prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof, wherein the patient has, prior to administration of the 5-MeO-DMT, taken part in a virtual reality (VR) experience designed to prepare the patient for psychedelic therapy.
In an embodiment, the method of treatment further comprises additional VR experiences to complement the PDT/psychedelic therapy.
In an embodiment, there is provided a prescription digital therapeutic (PDT) for use in a method of treatmentresistant depression treatment, wherein the method comprises administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof, wherein the patient has, prior to administration of the 5-MeO-DMT, taken part in a virtual reality (VR) experience designed to prepare the patient for psychedelic therapy.
In an embodiment, the patient is monitored by analysis of passively entered data. As used herein, "passively gathered data" refers to data which is gathered via a digital device. In one embodiment, the device is a smart phone and the data may be: accelerometer and/or gyroscope data as a measure of movement, GPS location data as a measure of movement, screen time data, Bluetooth interaction data, Wi-Fi network interaction data, communications activity data (e.g. messaging, voice calls, number, frequency, duration of inbound and outbound calls/text messages or instant messaging messages), app usage data (e.g. number of app opens, duration of use, type of app), human computer interaction pattern data (frequency, duration, speed of finger touches on a screen or speed of typing on a keyboard), sleep data (e.g. frequency, duration, quality of sleep as derived from light, phone usage, actigraphy). In one embodiment, the device is a wearable device, wherein the device measures one or more of: heart rate, respiratory rate, galvanic skin response, blood pressure and/or temperature. In such an embodiment, the passively gathered data is one or more of: heart rate data, respiratory rate data, galvanic skin response data, blood pressure data and/or temperature data. In an embodiment, the wearable device is an EEG. In an embodiment, the passively generated data is environmental data. In such an embodiment, the environmental data may be weather data.
In an embodiment, the patient is monitored by analysis of both passive and actively entered data. In an embodiment, the patient is monitored by analysis of data by machine learning algorithms. In an embodiment, the patient is monitored by analysis of data by statistical analyses. In an embodiment, the patient is monitored by analysis of data by statistical analyses and/or machine learning algorithms. Statistical analyses and/or machine learning algorithm(s) can be characterized by a learning style including any one or more of: supervised learning (e.g., using back propagation neural networks), unsupervised learning (e.g., K-means clustering), semi-supervised learning, reinforcement learning (e.g., using a Q-learning algorithm, using temporal difference learning, etc.), and any other suitable learning style.
Furthermore, any algorithm(s) can implement any one or more of: a regression algorithm, an instance-based method (e.g., k-nearest neighbour, learning vector quantization, self-organizing map, etc.), a regularization method, a decision tree learning method (e.g., classification and regression tree, chi-squared approach, random forest approach, multivariate adaptive approach, gradient boosting machine approach, etc.), a Bayesian method (e.g., naive Bayes, Bayesian belief network, etc.), a kernel method (e.g., a support vector machine, a linear discriminate analysis, etc.), a clustering method (e.g., k-means clustering), an associated rule learning algorithm (e.g., an Apriori algorithm), an artificial neural network model (e.g., a back-propagation method, a Hopfield network method, a learning vector quantization method, etc.), a deep learning algorithm (e.g., a Boltzmann machine, a convolution network method, a stacked auto-encoder method, etc.), a dimensionality reduction method (e.g., principal component analysis, partial least squares regression, etc.), an ensemble method (e.g., boosting, boot strapped aggregation, gradient boosting machine approach, etc.), and any suitable form of algorithm.
In an embodiment, there is provided a method of the use of 5-MeO-DMT benzoate, optionally the benzoate salt, in a method of treatment of a patient in need thereof, the method comprising the steps of:
Obtaining the following data on a patient: o Actively entered data by the patient and/or a clinician through a digital device; o Passively gathered data via a digital device such as a smartphone or a wearable worn or used by the patient;
Combining the data to create a knowledge graph of the individual;
Combining the data to generate the following measures and a report of potential treatment response: Probability of treatment response or non-response; Level of treatment response; Time to treatment response; Duration of effect; Probability of relapse; Time to relapse; Probability of adverse events; Optimal regimen (dose, frequency and duration);
Combining the above measures to determine response sub-types, determine whether to treat with 5-MeO- DMT benzoate and to categorise an individual to assign to a predefined or develop a custom treatment programme.
In an embodiment, the predefined or custom treatment programme determines the following: Dose and schedule; Wash-out from selective serotonin-reuptake inhibitors (SSRIs); Safety monitoring needed during wash-out period; Preparation and integration content to be delivered; Preparation and integration therapy to be delivered; Optimal number and duration of preparation and integration sessions with a therapist; Between session content and therapy to be delivered; In session experiential setting customisations (e.g. music); and/or Post-integration content and therapy to sustain or enhance response to 5-MEO-DMT and prevent relapse.
In an embodiment, the measures, report and recommendation may be sent to a clinician to inform the following decisions: Decision whether to treat with 5-MeO-DMT; Decision as to whether SSRI washout will be needed; Dose selection; Number of treatments needed; In-person and/or digital preparation and integration programme including content, number and duration of sessions; In-session experiential setting (e.g. music selection); Post-integration enhancement and/or maintenance programme.
In an embodiment, the measures may be sent to a computer platform/app/digital solution/system to influence automatically generated digital experiences such as: Preparation and integration digital therapy or content in- session or between sessions; In-session experiential setting (e.g. music selection); Post-integration response enhancement and/or maintenance programme; Automated reminders and alerts to clinician and/or patient to return for re-treatment.
In an embodiment, there is provided a computer system and set of digital devices to deliver tailored preparation, insession experience and integration content and therapy based on the profile of the individual patient. In an embodiment, there is provided a system to receive data, measures and the identified response profile for a patient and:
Map to one of a number of predefined treatment programmes that have been designed to deliver optimal outcomes for a given response profile;
Create a custom treatment programme designed to deliver optimal outcomes for a given individual;
Deliver the predefined or custom preparation via a digital device such as a smartphone, to support the patient in session with the clinician and between session, such as:
• Written and audio/visual content
• Therapy content and activities
Where the above information and therapy is designed to ensure the optimal mindset during administration of 5-MeO-DMT benzoate by:
• Ensuring the individual is in a relaxed and open mindset;
• Setting expectations regarding the unique experience of 5-MeO-DMT;
• Ensuring the individual is able to surrender and embrace the experience, in order to avoid negative experiences generated through resisting;
• Bringing to the front of mind topics and subject matter the individual would like to address;
• Addressing and alleviating fears and concerns.
In an embodiment, the optimal mindset is achieved by the use of: Videos and/or audio recordings with explanations and examples of the 5-MeO-DMT experience; Guided meditation and/or breathing exercises; Neuro/bio-feedback exercises; Therapy tasks, such as the Values Card Sort Task; Enabling the individual to capture notes and journal entries during and in-between sessions; Connecting the individual to a remote therapist; and/or Connecting the individual to others who have experienced treatment with 5-MeO-DMT.
In an embodiment, user engagement with such content (for example, app interaction patterns) is used to derive and/or update a prediction of treatment response or response profile. In an embodiment, there is provided a system for the measurement of a patient's response to 5-MeO-DMT therapy comprising:
A wearable device or access module and/or sensor, such as an electroencephalography (EEG) headset or smartwatch for the measuring of one or more of: o EEG o Basic physiology:
■ Heart rate
■ Respiratory rate
■ Blood pressure
■ Galvanic skin response;
A camera, microphone, access module and/or sensor in the treatment room measuring one or more of: o Eye-movement o Facial expression o Speech analysis o Body movements o Temperature;
A computer platform for receiving data regarding one or more of EEG, basic physiology, eye-movement, facial expressions, speech analysis, body movements and/or temperature and derive from said data the current treatment response, predict future treatment response and/or inform or update a patient response profile wherein based on the received data: i. real-time automated changes to the treatment setting are initiated such as adjustments of one or more of:
• Temperature;
• Lighting;
• Music/audio;
• Video;
• Virtual reality experience; and/or ii. The need for, number of and time until any additional doses is determined; and/or iii. The optimal dose for the patient is determined; and/or iv. The optimal number, frequency of and duration of post-treatment integration; and/or v. The optimal content and therapy needed for integration and post-integration to enhance or sustain any response;
Wherein the data, measures and/or updated treatment response profile is sent to:
A clinician via a graphical user interface (GUI); and/or
A patient via a GUI; and/or
A further computer platform.
In an embodiment, there is provided a method to support the immediate post-treatment integration period following 5-MeO-DMT treatment comprising the steps of: a. Passively capturing audio and visual data of a patient describing their treatment experience; b. Transcribing that data into text; c. Enable a user such as a clinician or patient to take photos of drawing or writing on paper; d. Transcribing patient or clinician generated photos or drawings or writing on paper to text or images; and e. Conducting statistical analysis on any text from steps (a) to (d) to derive features or measures of text.
Wherein the features or measures of the text are used to determine or update a prediction of response to treatment and thereby influence subsequent integration and a post-integration treatment programme. In an embodiment, there is provided a system for use in this method. In an embodiment, there is provided a method for delivering a predefined or custom integration programme, which is selected based on the individual's response profile, which itself is updated based on data collected during treatment with 5-MeO-DMT benzoate.
In an embodiment, the programme is delivered via a digital device, such as a smartphone. In an embodiment, the programme comprises content such as written and audio/visual content, therapy content and activities etc. In an embodiment, the programme content is designed to: a. Support the individual in recalling the experience; b. Support the individual in relating the experience to other aspects of their life, both prior to the experience and going forward; c. Support the individual to take positive, values-based actions intended to create a positive behavioural and emotional change; and d. Enable the individual to learn more about the treatment, their experience, and the experiences of others in order to make sense of it.
In an embodiment, the programme achieves its goals by: a. Delivering video, audio, written and visual content; b. Using the individual's response profile to suggest tailored content to the individual; c. Using the individual's app activity to suggest content to the individual; d. Enabling the individual to document and record thoughts and feelings and document plans or actions to take for the future; e. Enabling the user to review content created or recorded from preparation, in-session or the immediate post-session integration period; f. Connecting the individual to a remote therapist; and/or g. Connecting the individual to others such as peers who have experienced the same treatment.
In an embodiment, the method comprises the communication of the patient experience and learnings to other people that the patient identifies such as: a. Peers, i.e. strangers who have also experienced the treatment; b. Family and friends; c. The patient's usual clinician.
In an embodiment, the method comprises the analysis of actively entered and passively gathered data during the integration phase in order to continue to update the response profile to better estimate the long term response and likelihood of relapse. In an embodiment, there is provided a method of identifying ongoing treatment response, detecting and predicting relapse post the integration phase, whereby the method comprises the continued gathering of passive and actively entered data for N time after integration and updating a patient response profile model. In an embodiment, the method comprises indicating whether a measure is confirmed (actual) or predicted (predicted) and sending the measures or a report to: a. A clinical professional via a graphical user interface; b. Another individual via graphical user interface e.g. a peer; c. The patient themselves via a graphical user interface; and/or d. A computing platform.
In an embodiment, the measures are: a. Level of treatment response (actual) b. Time to treatment response (actual) c. Duration of effect (predicted to actual) d. Probability of relapse (predicted to actual) e. Time to relapse (predicted to actual) f. Probability of adverse events (predicted to actual) g. Optimal regimen (predicted or actual) i. Dose ii. Frequency iii. Duration
In an embodiment, the measures or report are sent: a. When any measure changes i. In any direction, by any degree; or ii. Outside of a defined threshold; b. When a particular measure changes i. In any direction, by any degree; or ii. Outside of a defined threshold; c. At a predetermined frequency e.g. daily d. When requested by a user e.g. a patient or a clinician; e. When requested by a computer system.
In an embodiment, when the recipient is a clinician, the measures or report informs a decision to: a. Deliver re-treatment with 5-MeO-DMT; b. Make contact via messaging or phone call; c. Schedule an in-person or virtual session with self or another clinician; d. Send digital content to the user to provide support; e. Send a message or email to the patient's usual clinician; and/or f. Change to a different treatment regime.
In an embodiment, when the recipient is a peer, the measures or report informs a decision to: a. Send a message to the patient; b. Comment on the report; or c. Schedule an audio or video call with the patient.
In an embodiment, when the recipient is the patient, the measures or report informs a decision to: a. Contact the clinician with regards to re-treatment; b. Contact the clinician with regards to changing treatment; c. Engage in digital therapy via a digital device; or d. Contact a peer via messaging, audio or video calling, via a digital device.
In an embodiment, a report is created that is updated on a regular basis to show the continuous experience of the individual over the time post treatment and any interventions delivered. As used herein, an "access module" refers to any hardware and/or software (or system thereof) that receives session data (e.g., raw session data and/or processed session data) and (i) processes the session data; and/or (ii) relays the session data to a remote monitor. In some embodiments, the access module receives the session data (e.g., raw session data) and processes the session data (e.g., to derive a patient response metric available to a remote monitor, physician, or clinical support staff). In some embodiments, the access module receives the session data (e.g., raw session data) and relays the session data to a remote monitor (e.g., via real-time stream). In some embodiments, the access module receives the session data (e.g., raw session data), processes the session data (e.g., to derive a patient response metric), and relays the processed session data to a remote monitor, physician, or clinical support staff. In some embodiments, the session data is "actively entered data". In some embodiments, the session data is "passively gathered data". As used herein, a "treatment setting" is a physical space (e.g., a room or a suite) which is regulated by clinical standards, e.g., for safety and/or data control. As used herein, a "physician" is a person who has a Doctor of Medicine degree (M.D.; such as a psychiatrist or psychotherapist) or Osteopathic Medicine degree (D.O.) who is legally authorized to practice medicine, such as a person who has a Ph.D. in clinical psychology (i.e., a clinical psychologist). As used herein, a "clinical practitioner" is a nurse practitioner, clinical social worker, or physician assistant who is authorized to practice within the scope of their practice as defined under state or local law. In some embodiments, a clinical practitioner is certified to address an adverse effect associated with administration of a psychotherapy.
As used herein, a "certified mental health practitioner" is a person authorized to practice in the field of mental health, such as a mental health nurse or psychotherapist. In some embodiments, a certified mental health practitioner is certified to address an adverse effect associated with administration of a psychotherapy. As used herein, an "attendant" is a person who is not a physician and who is physically present in the same room as the patient for at least a portion of the psychedelic therapy session. In some embodiments, the attendant may not be certified as a mental health practitioner, but has been qualified to be an attendant via participation in a training program for attendants, passing a certification exam, and/or participating in ongoing training (e.g., according to method or system of training as provided herein). As used herein, a "remote monitor" is a person who is not physically present in the same room as the patient for at least a portion of the psychedelic therapy session and who has access to a recording of the psychedelic therapy session and/or data regarding events which have occurred outside the therapy session, such data may be gathered by an app on one or more patient devices. In some instances, the remote monitor is not a physician. In other instances, the remote monitor is a physician. In some instances, the remote monitor is not a clinical practitioner. In other instances, the remote monitor is a clinical practitioner. In some instances, the remote monitor is certified, e.g., in clinical research, clinical trial management, etc.
As used herein, to "derive" a metric from a recording refers to the act of obtaining the metric using information provided by the recording, alone or in combination with additional information not provided by the recording (e.g., using a classifier or, alternatively, by comparing session data from a given psychoactive therapy session and/or data regarding events which have occurred outside the therapy session, such data may be gathered by an app on one or more patient devices to session data from a previous psychoactive therapy session and/or data regarding events which have occurred outside the therapy session, such data may be gathered by an app on one or more patient devices). For example, a patient response metric may be derived from a video recording by processing all or a portion of the video recording to obtain a measure of motor activity, and, if the measure of motor activity exceeds a predetermined threshold value by a factor of X, a patient response metric having a value of Y is derived. In such cases, the predetermined threshold may be set using a classifier (e.g., using a cross-validation approach with training data). One or more data sets from a recording may be input into an algorithm (e.g., an algorithm having preset and/or variable factors, e.g., a machine learning algorithm (e.g., a Random Forest or Support Vector Machine), used in accordance with methods known in the art and described herein), the product of which is a metric derived from the recording. In another example, session data from one or more psychoactive therapy sessions is compared to session data from one or more previous psychoactive therapy sessions (e.g., among the same patient).
As used herein, a "patient response metric" is a measure of the patient's response to the psychedelic therapy being administered, which can be derived from one or more parameters of session data. The response can be a therapy- induced altered state of consciousness, distress, anxiety, paranoia, dread, and/or other psychoactive drug effects (e.g., acute psychoactive drug effects). In some embodiments, a patient response metric discriminates between a psychopathology (e.g., bipolar disorder (e.g., bipolar mania) or schizophrenia) and a positive or adverse drug effect and serves as a predictor of treatment response. Patient response metrics include locomotion, unresponsiveness to a question, other language or behavioural characteristics, or a combination thereof. In some instances, the patient response metric is derived from multiple parameters, wherein the multiple parameters are obtained through one or more data streams (e.g., digitally recorded data (e.g., audio, video, and/or biometric data) and/or manually recorded data (e.g., data recorded by the attendant)). As used herein, an "aberrance" is information (e.g., session data) associated with a negative event, such as an adverse patient response or deviation from protocol during the session, e.g., misconduct by the attendant. In embodiments of the invention in which the aberrance is a deviation from protocol, the protocol (and deviation thereof) may be based on a predetermined risk management plan (e.g., a European Medicines Agency (EMA) Risk Management Plan and/or an FDA Risk Evaluation and Mitigation Strategy (REMS)).
As used herein, a "psychological disorder" refers to a condition characterized by a disturbance in one's emotional or behavioural regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function. Psychological disorders include, but are not limited to depressive disorders (major depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcoholism, tobacco abuse, or drug abuse)), and compulsive behaviour disorders (e.g., primary impulse-control disorders or obsessive- compulsive disorder). Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms. Psychological disorders also include repetitive body-focused behaviours, such as tic disorders (e.g., Tourette's syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skinpicking, or a chronic motor tic disorder). In some cases, development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self- esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses. Diagnostic guidance for psychological disorders can be found, for example, in the ICD-10 (The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).
As used herein, "remote intervention" refers to an intervention that is conducted by a physician (e.g., a psychiatrist) who is not physically present at the treatment setting (i.e., remote) at the time of the intervention. The physician may direct the treatment of a patient from a remote location, e.g., by authorizing treatment to be administered by a clinical practitioner or a certified mental health practitioner who is not a physician. Authorization may be granted from a physician to an attendant, a monitor, and/or another support staff member. In some instances, the physician remotely intervenes after being alerted by an attendant, a remote monitor, or another clinical support staff member. For example, in some embodiments, remote intervention includes authorization by a physician to a non-physician to intervene in the psychoactive therapy session, e.g., by administering a rescue drug, e.g., benzodiazepine. As used herein, "local intervention" refers to an intervention that is conducted by a physician (e.g., a psychiatrist) who is physically present at the treatment setting at the time of the intervention. In some instances, the physician is summoned to the treatment setting by an attendant, a remote monitor, or another clinical support staff member to locally intervene. As used herein, "well-being" refers to a positive state of health or comfort, e.g., relative to a reference population. As used herein "mental well-being" refers to a positive mental state, relative to a reference population. For example, in an individual having depression, low self-esteem, addiction, compulsion, or anxiety may experience an improvement in mental well-being in response to therapy aimed at improving mood, self-esteem, addiction, compulsion, or anxiety, respectively.
As used herein, "physical well-being" refers to one or more positive aspects of an individual's physical health. For example, an improvement of physical well-being includes alleviation of somatic symptoms associated with a psychological disorder, depression, addiction, compulsion, anxiety, or sexual dysfunction. Such symptoms include, for example, chronic pain, pain disorder, relational disorder, body dysmorphia, conversion (e.g., loss of bodily function due to anxiety), hysteria, neurological conditions without identifiable cause, or psychosomatic illness). As used herein, the term "treating" refers to administering a pharmaceutical composition for therapeutic purposes. To "treat a disorder" or use for "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease to ameliorate the disease or one or more symptoms thereof to improve the patient's condition. The methods of the invention can also be used as a primary prevention measure, i.e., to prevent a condition or to reduce the risk of developing a condition. Prevention refers to prophylactic treatment of a patient who may not have fully developed a condition or disorder, but who is susceptible to, or otherwise at risk of, the condition. Thus, in the claims and embodiments, the methods of the invention can be used either for therapeutic or prophylactic purposes.
The term "administration" or "administering" refers to a method of giving a dosage of a pharmaceutical composition to a subject, where the method is, e.g., oral, topical, transdermal, by inhalation, intravenous, intraperitoneal, intracerebroventricular, intrathecal, or intramuscular. As used herein, a "psychotherapy" refers to a nonpharmaceutical therapy in which the subject is psychologically engaged, directly or indirectly (e.g., by dialogue), in an effort to restore a normal psychological condition; to reduce the risk of developing a psychological condition, disorder, or one or more symptoms thereof; and/or to alleviate a psychological condition, disorder, or one or more symptoms thereof. Psychotherapy includes Behavioural Activation (BA), Cognitive Behavioural Therapy (CBT), Interpersonal psychotherapy (I T), Psychoanalysis, Hypnotherapy, Psychedelic Psychotherapy, Psycholytic Psychotherapy, and other therapies. In some embodiments, a subject undergoes psychotherapy in conjunction with (e.g., prior to, during, and/or after) a pharmaceutical therapy, such as a psychedelic therapy.
The present embodiments provide enhanced patient safety through unobtrusive monitoring with the capacity to alert clinicians to the emergence of psychotic-spectrum disorders related to (i) long-term low-to-sub perceptual use of 5-MeO-DMT, optionally the benzoate, and/or (ii) acute medium-to-high dose use of 5-MeO-DMT, optionally the benzoate. In particular, the invention provides an adjunctive use of a mobile health software application and supportive infrastructure to enhance patient safety in therapeutic regimens involving treatment with 5-MeO-DMT, optionally the benzoate.
In one aspect, the invention features a method of screening a candidate for treatment with a 5-MeO-DMT, optionally the benzoate. The method includes (i) obtaining a language sample from a treatment candidate; (ii) deriving one or more language characteristics from the language sample; and (iii) based on the one or more language characteristics, determining a measure of risk. The measure of risk correlates with a risk of precipitating or exacerbating psychosis, hypomania, or mania in the candidate. In some embodiments, the method further includes sending a report to a third party. The third party can be, for example, a clinical professional (e.g., a physician, pharmacist, administrative professional, nurse, support professional, or caretaker). In other embodiments, the third party can be a computing platform (e.g., a computer database accessible to one or more clinical professionals, such as pharmacy staff, who may access the computing platform to obtain instructions to fill a psychedelic prescription or not). Thus, in some embodiments, the report informs a decision to prescribe or administer the 5-MeO-DMT, optionally the benzoate. For example, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party that a the therapy should not be prescribed or administered. In some embodiments, the report informs a dosing regimen for the therapy. For example, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is below a predetermined threshold or a reference value, the report instructs a third party to increase the dose. Conversely, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party to decrease the dose.
In some embodiments of any of the methods described herein, the candidate or patient has been characterized as unlikely to have or develop a paranoid ideation or propensity toward paranoid thinking, paranoid personality disorder, a personality disorder, an intellectual disability (e.g., intellectual developmental disorder), or bipolar disorder. In some embodiments, any of the methods of the invention include screening the candidate for a likelihood of having or developing a paranoid ideation or propensity toward paranoid thinking, paranoid personality disorder, a personality disorder, an intellectual disability (e.g., intellectual developmental disorder), or bipolar disorder. Methods of screening for such disorders and characteristics can be adapted for the present invention from methods known in the art, such as industry-standard questionnaires. In some embodiments, such screening methods can be conducted by a clinician (e.g., in person). Additionally or alternatively, screening methods can be conducted using a mobile device configured to perform any one or more of the methods provided herein.
In an aspect, the invention features a method of reducing a risk of developing psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT (optionally the benzoate salt), the method including: (i) obtaining a language sample from the patient undergoing treatment with 5-MeO-DMT (optionally the benzoate salt); (ii) deriving one or more characteristics of the language sample; (iii) based on the one or more characteristics, determining a measure of risk, wherein the measure of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and (iv) based on the measure of risk, recommending whether to suspend the treatment (e.g., as part of a report sent to a third party).
Thus, the method further includes sending a report to a third party. The third party can be, for example, a clinical professional (e.g., a physician, pharmacist, administrative professional, nurse, support professional, or caretaker). In other embodiments, the third party can be a computing platform (e.g., a computer database accessible to one or more clinical professionals, such as pharmacy staff, who may access the computing platform to obtain instructions to fill a prescription or not). Thus, in some embodiments, the report informs a decision to prescribe or administer the therapy. For example, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party that the therapy should not be prescribed or administered.
In an aspect, the invention provides a method of assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT (optionally the benzoate salt), the method including: (i) providing a plurality of measures of risk, each measure of risk derived from one or more characteristics of a language sample obtained from the patient, wherein each measure of risk is associated with a different treatment time point (e.g., daily, every 2 days, every 3 days, every 4 days, every 5 days, weekly, monthly, twice per month, twice per week, or three times per week); and (ii) comparing two or more of the plurality of measure of risk (e.g., consecutive or non-consecutive (e.g., latest-to-earliest time point)) to obtain a differential measure of risk, wherein the patient is identified as at risk of precipitating or exacerbating psychosis, hypomania, or mania if the differential measure of risk exceeds a predetermined threshold. The method further includes sending a report to a third party. The third party can be, for example, a clinical professional (e.g., a physician, pharmacist, administrative professional, nurse, support professional, or caretaker). In other embodiments, the third party can be a computing platform (e.g., a computer database accessible to one or more clinical professionals, such as pharmacy staff, who may access the computing platform to obtain instructions to fill a prescription or not). Thus, in some embodiments, the report informs a decision to prescribe or administer the therapy. For example, if the differential risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party that a the psychedelic therapy should not be prescribed or administered.
In an aspect, the invention features a method of providing a regimen of 5-MeO-DMT (optionally the benzoate salt) therapy to a patient, the method including : (i) providing a differential measure of risk obtained by comparing two or more measures of risk, each measure of risk derived from one or more language characteristics of a language sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient, and wherein each measure of risk is associated with a different treatment time point; and (ii) suspending the therapy if the differential measure of risk exceeds a predetermined threshold.
In some embodiments of any of the methods described herein, the patient has been screened for one or more adverse effects associated with 5-MeO-DMT (optionally the benzoate salt) (e.g., using screening methods known in the art). Additionally or alternatively, a method of the invention may include screening the patient for one or more adverse effects associated with 5-MeO-DMT (optionally the benzoate salt). Adverse effects that can be screened for include, e.g., depersonalization, dissociation, derealization, hallucinogenic or psychoactive abuse, hallucinogen-use disorders, hallucinogen-induced disorders, high-risk behaviours, and mania. Methods of screening for such disorders and characteristics can be adapted for the present invention from methods known in the art, such as industrystandard questionnaires. In some embodiments, such screening methods can be conducted by a clinician (e.g., in person). Additionally or alternatively, screening methods can be conducted using a mobile device configured to perform any one or more of the methods provided herein.
In some embodiments, the method further includes administering 5-MeO-DMT (optionally the benzoate salt) (or recommending administration) if the screening indicates that the patient is not experiencing the one or more adverse effects (e.g., presently experiencing one or more adverse effects or has experienced one or more adverse effects during the course of treatment), or if the screening does not indicate that the patient is experiencing the one or more adverse effects (e.g., presently experiencing one or more adverse effects or has experienced one or more adverse effects during the course).
Methods of the invention additionally provide means for determining whether the patient is complying with the prescribed regimen of 5-MeO-DMT (optionally the benzoate salt) therapy. In some embodiments, the method further includes assessing a measure of compliance. In some embodiments, the method further includes assessing a measure of abuse of 5-MeO-DMT (optionally the benzoate salt). Measures of compliance and/or abuse can be derived from one or more digital readouts using the methods and systems of the invention, e.g., by observing a level of a biomarker, for example, a level of a target molecule present in a body sample obtained from the patient (e.g., a level of 5-MeO-DMT (optionally the benzoate salt), a metabolite, or another molecule that correlates positively or negatively with the level of 5-MeO-DMT (optionally the benzoate salt) in the patient).
In some embodiments, methods of the invention include determining a frequency of retreatment of the patient with the 5-MeO-DMT (optionally the benzoate salt). The frequency of retreatment can be determined by (i) providing a measure of efficacy correlated with a positive therapeutic response in the patient to the 5-MeO-DMT (optionally the benzoate salt); (ii) providing a measure of risk correlated with a risk of precipitating or exacerbating a disease state associated with stress or a psychopathology; and (iii) based on steps (i) and (ii) (e.g., weighing the measure of risk against the measure of efficacy), determining a frequency of retreatment with the 5-MeO-DMT (optionally the benzoate salt). The measure of efficacy, the measure of risk, or both, can be output from (and/or confirmed by) a clinical assessment, e.g., using a software configured to communicate with a mobile device or any of the methods or systems described herein (e.g., wherein one or more factors of the clinical assessment include a language characteristic, a behavioural characteristic, and/or a biomarker), or directly by a clinician using known methods, such as industry-standard questionnaires. In some embodiments, the frequency of retreatment is from bi-weekly to annually (e.g., bi-weekly, monthly, four times per year, twice annually, or annually). In some embodiments, a patient is retreated or redosed (e.g., to adjust the amount per dose or frequency of dosing) upon detecting a deterioration in mental health. For example, a patient that is undergoing treatment or has been treated for any of the diseases or disorders described herein can be retreated or redosed for the disease or disorder upon detection of an increase in one or more symptoms associated with the disease or disorder. The detection can be by any of the methods described herein, for example, by obtaining a language characteristic, a behavioural characteristic, or a digital biomarker indicative of the disease or disorder (e.g., through a digital clinical assessment).
In some embodiments, the method of the invention include adjusting the dose and/or frequency of treatment with the 5-MeO-DMT (optionally the benzoate salt) based on one or more of any of the behavioural characteristics, language characteristics, and/or biomarkers described herein, or any of the measures of risk, compliance, or abuse described herein. In some embodiments, the dose is increased (e.g., to address a low measure of efficacy or a high measure of risk). In other embodiments, the dose is decreased (e.g., to decrease a measure of risk when a measure of efficacy indicates that the treatment is working, or to address a hilgh level of one or more biomarkers). In an aspect, the invention features a method of administering a 5-MeO-DMT (optionally the benzoate salt) to a patient in need thereof, the method including: (i) obtaining one or more measures of risk derived from one or more language characteristics of a language sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and (ii) administering the 5-MeO-DMT (optionally the benzoate salt) if the measure of risk is below a predetermined threshold. In an aspect, the invention features a method of characterizing the influence of a 5-MeO-DMT (optionally the benzoate salt) on the perception of a patient administered therewith, the method including: (i) obtaining a language sample from the patient; (ii) providing one or more language characteristics of the language sample; and (ii) based on the one or more language characteristics, determining a measure of psychedelic influence, wherein the measure of psychedelic influence correlates with the influence of the psychedelic compound on the perception of the patient.
A method of any of the preceding aspects may further include, in response to determining that a candidate has a high measure of risk, prompting an ecological momentary assessment (EMA) of the candidate, e.g., to confirm or further inform a decision regarding a clinical path forward. In some embodiments of any of the preceding aspects, the language sample is elicited by a digital prompt, a questionnaire, a clinician administered interview. In some embodiments, the language sample may be, or may be obtained from a dream report, a description of a picture, a thematic apperception test, or a neutral text reading. In some embodiments, the language sample is obtained by passive acquisition (e.g., constant or arbitrary monitoring of outgoing audio data or text data). In some embodiments, the language sample is a text sample and/or an audio sample. In some embodiments, the audio sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises one or more acoustic features (e.g., a measure of irregular pitch (e.g., standard variance of pitch), zero-crossing rate, kurtosis energy, harmonics-to-noise ratio (HNR), mel-frequency cepstral coefficients (MFCC), and frame energy). In some embodiments, the audio sample is transcribed into text.
In some embodiments, the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of semantic coherence. A low measure of semantic coherence may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of syntactic complexity. A low measure of syntactic complexity may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of maximum phrase length. A low measure of maximum phrase length may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of lexicon breadth and/or lexicon depth. A low measure of lexicon breadth or depth may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of logorrhea. A high measure of logorrhea may be positively correlated with the risk of developing hypomania or mania. In some embodiments, the one or more language characters include a measure of psychometrics (e.g., latent inhibition). In some embodiments, the one or more language characters include a measure of flight of thought. A high measure of flight of thought may be positively correlated with the risk of developing hypomania or mania. In some embodiments, the one or more language characters include a measure of recursiveness. A high measure of recursiveness may be positively correlated with the risk of developing hypomania or mania.
In some embodiments, the language sample is analyzed to derive speech graph attributes. The speech graph attributes can be obtained for all or a portion of the words used in the speech sample as an input, for example, to a machine learning algorithm. In any of the preceding aspects, one or more behavioural characteristics further informs the measure of risk. In some embodiments, the one or more behavioural characteristics are derived from a telephone record. For example, the one or more behavioural characteristics derived from a telephone record may be a number or frequency of outgoing calls or messages, a number or frequency of incoming calls or messages, a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages, a duration of one or more calls, a length of one or more messages, a number of new phone numbers, a number of changes in cell tower IDs, or a number of unique cell tower IDs. In some embodiments, a number or frequency of outgoing calls or messages is positively correlated with the risk of developing hypomania or mania. In some embodiments, a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages is positively correlated with the risk of developing hypomania or mania. In some embodiments, a duration of one or more calls is positively correlated with the risk of developing hypomania or mania. In some embodiments, the length of one or more messages is positively correlated with the risk of developing hypomania or mania. In some embodiments, a number of new phone numbers is positively correlated with the risk of developing hypomania or mania.
In some embodiments, the one or more behavioural characteristics include a number or frequency of instances in which a mobile device screen is turned on. In some instances, the one or more behavioural characteristics include a measure of activity detected by a sensor (e.g., an antenna on a mobile device, e.g., a smartphone). For example, the sensor may be in communication with a global positioning system (GPS). In some embodiments, the measure of activity is a measure of mobility (i.e., change in geographical location, e.g., as monitored by GPS). In some embodiments, a high measure of mobility is positively correlated with the risk of developing hypomania or mania. In some embodiments, the sensor is an accelerometer (e.g., as part of the mobile device). In some embodiments, the measure of activity comprises a measure of movement. In some embodiments, the measure of movement is positively correlated with the risk of developing psychosis, hypomania, or mania. In some embodiments, the sensor is or is in communication with a wireless network hub (e.g., Amazon Alexa or Google Home). Any behavioural characteristics detectable by the wireless network hub can be relayed to the systems of the present invention and can thus be incorporated into the methods provided herein. In some embodiments, the measure of movement is a speed of typing. In some embodiments, a behavioural characteristic describes a patient's behaviour on a computer or mobile device, such as a phone. For example, a behavioural characteristic can be derived from one or more human computer interactions (e.g., swipes, taps, and keystroke events) or combination or pattern thereof. In some embodiments, the one or more behavioural characteristics are derived from a frequency, duration, or quality of sleep. For example, the measure of frequency, duration, or quality of sleep can be derived from a frequency and/or duration of light exposure (e.g., by a light sensor on a mobile device or any device in communication with a wireless network hub), frequency or overall quantity of movement detected from movement sensors, or activity levels obtained from any other sensor described here (e.g., mobile device usage, such as onscreen time). In an aspect, the invention features a method of monitoring a 5-MeO-DMT (optionally the benzoate salt)'s effect on a patient's perception, for example, to inform a safe time of release from a supervised facility. Provided herein is a method of characterizing the influence of a 5-MeO-DMT (optionally the benzoate salt) on the perception of a patient administered therewith, the method including: (i) obtaining a language sample from the patient; (ii) providing one or more language characteristics of the language sample; and (ii) based on the one or more language characteristics, determining a measure of psychedelic influence, wherein the measure of psychedelic influence correlates with the influence of the psychedelic therapy on the perception of the patient. In some embodiments, the 5-MeO-DMT (optionally the benzoate salt) is administered on an in-patient basis. In such instances, the 5-MeO-DMT (optionally the benzoate salt) may be administered in a perceptible dose. In other embodiments, the 5-MeO-DMT (optionally the benzoate salt) is administered on an out-patient basis, and the 5- MeO-DMT (optionally the benzoate salt) may be administered in a sub-perceptible dose or a perceptible dose. In some embodiments, the method further comprises providing a notification based on the influence of a 5-MeO-DMT (optionally the benzoate salt) on the perception of the patient. In some embodiments, the notification informs a clinician's decision of when drug-induced alterations in perception and cognition of a patient receiving treatment involving a 5-MeO-DMT (optionally the benzoate salt) have returned to baseline or to a sufficiently low level. In some embodiments, the language sample is analyzed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of semantic proximity to one or more dimensions or facets related to an influence of a 5-MeO-DMT (optionally the benzoate salt) (e.g., as described in the 5D-ASC rating scale). In some embodiments, a measure of semantic proximity to one or more concepts related to an influence of a 5- MeO-DMT (optionally the benzoate salt) is positively correlated with the influence of the psychedelic therapy on the perception of the patient.
In an aspect, the invention provides a method of screening a candidate for treatment with a 5-MeO-DMT (optionally the benzoate salt), the method including: (i) obtaining a behavioural sample from a candidate (e.g., a candidate who has not begun a regimen involving psychedelic therapy); (ii) deriving one or more behavioural characteristics from the behavioural sample; and (iii) based on the one or more behavioural characteristics, determining a measure of risk, wherein the measure of risk correlates with a risk of precipitating or exacerbating psychosis, hypomania, or mania in the candidate. In some embodiments, the method further includes sending a report to a third party. The third party can be, for example, a clinical professional (e.g., a physician, pharmacist, administrative professional, nurse, support professional, or caretaker). In other embodiments, the third party can be a computing platform (e.g., a computer database accessible to one or more clinical professionals, such as pharmacy staff, who may access the computing platform to obtain instructions to fill a psychedelic prescription or not). Thus, in some embodiments, the report informs a decision to prescribe or administer the psychedelic therapy. For example, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party that a the psychedelic therapy should not be prescribed or administered. In some embodiments, the report informs a dosing regimen for the psychedelic therapy. For example, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is below a predetermined threshold or a reference value, the report instructs a third party to increase the dose of 5-MeO-DMT (optionally the benzoate salt). Conversely, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party to decrease the dose of 5-MeO-DMT (optionally the benzoate salt).
In an aspect, the invention features a method of reducing a risk of developing psychosis, hypomania, or mania in a patient undergoing treatment with a 5-MeO-DMT (optionally the benzoate salt), the method including: (i) obtaining a behavioural sample from the patient undergoing treatment with a 5-MeO-DMT (optionally the benzoate salt); (ii) deriving one or more characteristics of the behavioural sample; (iii) based on the one or more characteristics, determining a measure of risk, wherein the measure of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and (iv) based on the measure of risk, recommending whether to suspend the treatment with a 5-MeO-DMT (optionally the benzoate salt). In some embodiments, the method further includes sending a report to a third party. The third party can be, for example, a clinical professional (e.g., a physician, pharmacist, administrative professional, nurse, support professional, or caretaker). In other embodiments, the third party can be a computing platform (e.g., a computer database accessible to one or more clinical professionals, such as pharmacy staff, who may access the computing platform to obtain instructions to fill a psychedelic prescription or not). Thus, in some embodiments, the report informs a decision to prescribe or administer the psychedelic therapy. For example, if the risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party that a the psychedelic therapy should not be prescribed or administered.
In an aspect, the invention provides a method of assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with a 5-MeO-DMT (optionally the benzoate salt), the method including: (i) providing a plurality of measures of risk, each measure of risk derived from one or more characteristics of a behavioural sample obtained from the patient, wherein each measure of risk is associated with a different treatment time point (e.g., daily, every 2 days, every 3 days, every 4 days, every 5 days, weekly, monthly, twice per month, twice per week, or three times per week); and (ii) comparing two or more of the plurality of measures of risk (e.g., consecutive or non-consecutive (e.g., latest-to-earliest time point)) to obtain a differential measure of risk, wherein the patient is identified as at risk of precipitating or exacerbating psychosis, hypomania, or mania if the differential measure of risk exceeds a predetermined threshold. The method further includes sending a report to a third party. The third party can be, for example, a clinical professional (e.g., a physician, pharmacist, administrative professional, nurse, support professional, or caretaker). In other embodiments, the third party can be a computing platform (e.g., a computer database accessible to one or more clinical professionals, such as pharmacy staff, who may access the computing platform to obtain instructions to fill a psychedelic prescription or not). Thus, in some embodiments, the report informs a decision to prescribe or administer the psychedelic therapy. For example, if the differential risk of precipitating or exacerbating psychosis, hypomania, or mania is above a predetermined threshold or a reference value, the report instructs a third party that a the psychedelic therapy should not be prescribed or administered.
In an aspect, the invention features a method of providing a regimen of psychedelic therapy to a patient, the method including : (i) providing a differential measure of risk obtained by comparing two or more measures of risk, each measure of risk derived from one or more behavioural characteristics of a behavioural sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient, and wherein each measure of risk is associated with a different treatment time point; and (ii) suspending the psychedelic therapy if the differential measure of risk exceeds a predetermined threshold. In an aspect, the invention features a method of administering a 5-MeO-DMT (optionally the benzoate salt) to a patient in need thereof, the method including: (i) obtaining one or more measures of risk derived from one or more behavioural characteristics of a behavioural sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and (ii) administering the 5-MeO-DMT (optionally the benzoate salt) if the measure of risk is below a predetermined threshold.
A method of any of the preceding aspects may further include, in response to determining that a candidate has a high measure of risk, prompting an ecological momentary assessment (EMA) of the candidate, e.g., to confirm or further inform a decision regarding a clinical path forward. In some embodiments of any of the preceding aspects, the one or more behavioural characteristics are derived from a telephone record. For example, the one or more behavioural characteristics derived from a telephone record may be a number or frequency of outgoing calls or messages, a number or frequency of incoming calls or messages, a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages, a duration of one or more calls, a length of one or more messages, a number or frequency of newly added contacts, a number of changes in cell tower IDs, or a number of unique cell tower IDs. In some embodiments, a number or frequency of outgoing calls or messages is positively correlated with the risk of developing hypomania or mania. In some embodiments, a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages is positively correlated with the risk of developing hypomania or mania. In some embodiments, a duration of one or more calls is positively correlated with the risk of developing hypomania or mania. In some embodiments, the length of one or more messages is positively correlated with the risk of developing hypomania or mania. In some embodiments, a number of new phone numbers is positively correlated with the risk of developing hypomania or mania.
In some embodiments, the one or more behavioural characteristics include a number or frequency of instances in which a mobile device screen is turned on. In some instances, the one or more behavioural characteristics include a measure of activity detected by a sensor (e.g., an antenna on a mobile device, e.g., a smartphone). For example, the sensor may be in communication with GPS. In some embodiments, the measure of activity is a measure of mobility (i.e., change in geographical location, e.g., as monitored by GPS). In some embodiments, a high measure of mobility is positively correlated with the risk of developing hypomania or mania. In some embodiments, the sensor is an accelerometer (e.g., as part of the mobile device). In some embodiments, the measure of activity comprises a measure of movement. In some embodiments, the measure of movement is positively correlated with the risk of developing psychosis, hypomania, or mania. In some embodiments, the sensor is or is in communication with a wireless network hub (e.g., Amazon Alexa or Google Home). Any behavioural characteristics detectable by the wireless network hub can be relayed to the systems of the present invention and can thus be incorporated into the methods provided herein. In some embodiments of any of the preceding methods, the measure of risk is further based on one or more language characteristics derived from a language sample. The language sample may be elicited by a digital prompt, a questionnaire, or a clinician administered interview. In some embodiments, the language sample is, or may be derived from, a dream report, a description of a picture, a thematic apperception test, or a neutral text reading. In some embodiments, the language sample is obtained by passive acquisition (e.g., constant or arbitrary monitoring of outgoing audio data or text data). In some embodiments, the language sample is a text sample and/or an audio sample. In some embodiments, the audio sample is analyzed to derive the one or more language characteristics, wherein the one or more language characteristics comprises one or more acoustic features (e.g., a measure of irregular pitch (e.g., standard variance of pitch), zero-crossing rate, kurtosis energy, HNR, mel- frequency cepstral coefficients MFCC, and frame energy). In some embodiments, the audio sample is transcribed into text.
In some embodiments, the language sample is analyzed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of semantic coherence. A low measure of semantic coherence may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of syntactic complexity. A low measure of syntactic complexity may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of maximum phrase length. A low measure of maximum phrase length may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of lexicon breadth and/or lexicon depth. A low measure of lexicon breadth or depth may be positively correlated with the risk of developing psychosis. In some embodiments, the one or more language characters include a measure of logorrhea. A high measure of logorrhea may be positively correlated with the risk of developing hypomania or mania. In some embodiments, the one or more language characters include a measure of psychometrics (e.g., latent inhibition). In some embodiments, the one or more language characters include a measure of flight of thought. A high measure of flight of thought may be positively correlated with the risk of developing hypomania or mania. In some embodiments, the one or more language characters include a measure of recursiveness. A high measure of recursiveness may be positively correlated with the risk of developing hypomania or mania.
In any of the preceding aspects, the measure of risk may be further based on a result of an EMA. In some embodiments, the measure of risk refers to a risk or precipitating or exacerbating hypomania or mania, and the EMA is a psychopathology questionnaire configured to assess hypomania or mania. In such instances, the EMA can be the Hypomania/Mania Symptom Checklist (HCL-32), the Clinician-Administered Rating Scale for Mania (CARS-M), the Young Mania Rating Scale (YMRS), or an equivalent variant thereof. In other embodiments, the measure of risk refers to a risk of precipitating or exacerbating psychosis, and the EMA is a psychopathology questionnaire configured to assess psychosis (e.g., the psychosis screening questionnaire, the Schizophrenia Test and Early Psychosis Indicator (STEPI), the Cognitive Biases Questionnaire for psychosis (CBQp), or an equivalent variant thereof).
In any of the preceding aspects, the measure of risk can be determined using a machine learning algorithm. In some embodiments, the measure of risk is determined using a cluster model (e.g., a supervised cluster model or an unsupervised cluster model). The measure of risk may be determined using a Random Forest classifier or a within- patient Naive Bayes classifier. In some embodiments, the measure of risk is determined based on a change of one or more of the characteristics relative to a reference characteristic (e.g., a subject's baseline measurement of the characteristic obtained from the patient at an earlier time point or a cumulative value derived from a plurality of individuals (e.g., healthy individuals)). In some embodiments, the reference characteristic is a predetermined threshold.
In some embodiments of any of the preceding aspects, the psychedelic therapy is being administered for treatment of condition (e.g., a chronic condition). In some embodiments, the condition is an inflammatory-related condition. In some embodiments, the condition is Alzheimer's disease. In some embodiments, the condition is depression (e.g., major depression, melancholic depression, atypical depression, or dysthymia). In some embodiments, the condition is a psychological disorder selected from the group consisting of an anxiety disorder, an addiction, a compulsive behaviour disorder, or a symptom thereof. In some embodiments, the 5-MeO-DMT (optionally the benzoate salt) is being administered for improvement of mood or enhancement of performance. In some embodiments, the 5-MeO- DMT (optionally the benzoate salt) is being administered for treatment of stress, treatment of anxiety, treatment of addiction, treatment of depression, or treating of a compulsive behaviour. In some embodiments, the psychedelic therapy is being administered for treatment to improve the mental well-being of a patient. In some embodiments, the psychedelic therapy is being administered to reduce the risk of occurrence or reoccurrence of a psychopathology.
In some embodiments, the psychedelic therapy is part of a complex therapy, wherein the patient is additionally being treated with a psychotherapy. In some embodiments, the psychotherapy comprises behavioural activation therapy, talk therapy, existential therapy, and/or self-actualization therapy. For example, the behavioural activation therapy can be brief behavioural activation for depression (BATD). In some embodiments, the complex therapy is provided to the patient in a specialized treatment facility. In some embodiments of any of methods described herein, the candidate or patient has a neurodegenerative disease (e.g., Alzheimer's disease). In such embodiments, the methods of the invention can be performed after the patient has undergone one or more cognitive assessments. Alternatively, the method includes conducting one or more cognitive assessments on the patient. In some embodiments, the treatment is discontinued based on a negative result of the cognitive assessment (i.e., a result associated with drug-related brain decline). In some embodiments, the cognitive assessment is a mini-mental state examination (MMSE), the Montreal cognitive assessment (MOCA), or the Alzheimer's disease assessment scale - cognitive subscale (ADAS-Cog).
Non-limitinci embodiments may include:
Embodiment 1: A method of screening a candidate for treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the method comprising:
(i) obtaining a language sample from a treatment candidate, wherein the candidate has not begun treatment with 5-MeO-DMT, optionally the benzoate salt;
(ii) deriving one or more language characteristics from the language sample; and
(iii) based on the one or more language characteristics, determining a measure of risk, wherein the measure of risk correlates with a risk of precipitating or exacerbating psychosis, hypomania, or mania in the candidate.
2. The method of embodiment 1, further comprising sending a report to a third party. 3. The method of embodiment 2, wherein the third party is a clinical professional. 4. The method of embodiment 3, wherein the clinical professional is a physician, pharmacist, administrative professional, nurse, support professional, or caretaker. 5. The method of embodiment 2, wherein the third party is a computing platform. 6. The method of any one of embodiments 2-5, wherein the report informs a decision to prescribe or administer the psychedelic therapy. 7. The method of any one of embodiments 2-6, wherein the report informs a dosing regimen for the psychedelic therapy. 8. The method of any one of embodiments 1 -7, wherein the candidate has been characterized as unlikely to have or develop paranoid ideation, paranoid personality disorder, a personality disorder, an intellectual disability, or bipolar disorder. 9. The method of any one of embodiments 1 -7, further comprising screening the candidate for a likelihood of having or developing paranoid ideation, paranoid personality disorder, a personality disorder, an intellectual disability, or bipolar disorder. 10. A method of reducing a risk of developing psychosis, hypomania, or mania in a patient undergoing treatment with a 5-MeO-DMT (optionally the benzoate salt), the method comprising:
(i) obtaining a language sample from the patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT;
(ii) deriving one or more characteristics of the language sample;
(iii) based on the one or more characteristics, determining a measure of risk, wherein the measure of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and
(iv) based on the measure of risk, recommending whether to suspend the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT.
11. The method of embodiment 10, further comprising sending a report to a third party. 12. The method of embodiment 11, wherein the third party is a clinical professional. 13. The method of embodiment 12, wherein the clinical professional is a physician, pharmacist, administrative professional, nurse, support professional, or caretaker. 14. The method of embodiment 11, wherein the third party is a computing platform. 15. A method of assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO- DMT, optionally the benzoate salt of 5-MeO-DMT, the method comprising: (i) providing a plurality of measures of risk, each measure of risk derived from one or more characteristics of a language sample obtained from the patient, wherein each measure of risk is associated with a different treatment time point; and
(ii) comparing two or more of the plurality of measure of risk to obtain a differential measure of risk, wherein the patient is identified as at risk of precipitating or exacerbating psychosis, hypomania, or mania if the differential measure of risk exceeds a predetermined threshold.
16. The method of embodiment 15, further comprising sending one or more reports to a third party. 17. The method of embodiment 16, wherein the third party is a clinical professional. 18. The method of embodiment 17, wherein the clinical professional is a physician, pharmacist, administrative professional, nurse, support professional, or caretaker. 19. The method of embodiment 18, wherein the third party is a computing platform. 20. The method of embodiment 19, wherein the one or more reports recommends suspending the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, if the differential risk measure exceeds the predetermined threshold.
21. A method of providing a regimen of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy to a patient, the method comprising:
(i) providing a differential measure of risk obtained by comparing two or more measures of risk, each measure of risk derived from one or more language characteristics of a language sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient, and wherein each measure of risk is associated with a different treatment time point; and
(ii) suspending the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy if the differential measure of risk exceeds a predetermined threshold.
22. The method of any one of embodiments 10-21, wherein the patient has been screened for one or more adverse effects associated with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, wherein the one or more adverse effects are selected from the group consisting of depersonalization, dissociation, derealisation, hallucinogenic or psychoactive abuse, a hallucinogen-use disorder, a hallucinogen-induced disorder, a high-risk behaviour, and mania.
23. The method of any one of embodiments 10-21, further comprising screening the patient for one or more adverse effects associated with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, wherein the one or more adverse effects are selected from the group consisting of depersonalization, dissociation, derealisation, hallucinogenic or psychoactive abuse, a hallucinogen-use disorder, a hallucinogen-induced disorder, a high-risk behaviour, and mania.
24. The method of embodiment 22 or 23, further comprising administering 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, if the screening indicates that the patient is not experiencing the one or more adverse effects.
25. The method of any one of embodiments 10-24, further comprising assessing a measure of compliance with, or abuse of, 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT. 26. The method of embodiment 25, wherein the measure of compliance with, or abuse of, the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, is derived from a biomarker. 27. The method of any one of embodiments 10-26, further comprising determining a frequency of retreatment of the patient with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, wherein the frequency of retreatment is determined by:
(i) providing a measure of efficacy correlated with a positive therapeutic response in the patient to 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT;
(ii) providing a measure of risk correlated with a risk of precipitating or exacerbating a disease state associated with stress or a psychopathology; and
(iii) based on steps (i) and (ii), determining a frequency of retreatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, wherein the measure of efficacy and/or the measure of risk is an output from a clinical assessment.
28. A method of determining a frequency of retreatment of a patient with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the method comprising:
(i) providing a measure of efficacy correlated with a positive therapeutic response in the patient to the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT;
(ii) providing a measure of risk correlated with a risk of precipitating or exacerbating a disease state associated with stress or a psychopathology; and
(iii) based on the measure of efficacy and the measure of risk, determining a frequency of retreatment with 5-MeO- DMT, optionally the benzoate salt of 5-MeO-DMT, wherein the measure of efficacy and/or the measure of risk is an output from a clinical assessment. 29. A method of retreating or redosing a patient for a disease or disorder for which the patient is being treated with, or has been previously treated with, 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the method comprising:
(i) detecting an increase in one or more symptoms of a condition in the patient, wherein the patient has undergone a digital clinical assessment to obtain a language characteristic, a behavioural characteristic, and/or a biomarker; and
(ii) retreating or redosing the patient with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, for the condition.
30. The method of embodiment 29, wherein the condition is associated with deterioration of mental health. 31. The method of embodiment 27 or 28, wherein one or more factors of the clinical assessment comprise a language characteristic, a behavioural characteristic, and/or a biomarker. 32. The method of embodiment 30 or 31, wherein the frequency of retreatment is from bi-weekly to annually. 33. The method of any one of embodiments 10-26, further comprising adjusting the dose and/or frequency of treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, based on one or more behavioural characteristics, language characteristics, and/or biomarkers. 34. A method of administering 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, to a patient in need thereof, the method comprising:
(i) obtaining one or more measures of risk derived from one or more language characteristics of a language sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and
(ii) administering 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, if the measure of risk is below a predetermined threshold.
35. A method of characterizing the influence of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, on the perception of a patient administered therewith, the method comprising:
(i) obtaining a language sample from the patient;
(ii) providing one or more language characteristics of the language sample; and
(ii) based on the one or more language characteristics, determining a measure of psychedelic influence, wherein the measure of psychedelic influence correlates with the influence of 5-MeO-DMT, optionally the benzoate salt of 5- MeO-DMT, on the perception of the patient.
36. The method of any one of embodiments 1 -35, further comprising, in response to determining that a candidate has a high measure of risk, prompting an ecological momentary assessment (EMA) of the candidate. 37. The method of any one of embodiments 1 -36, wherein the language sample is elicited by a digital prompt, a questionnaire, or a clinician administered interview. 38. The method of any one of embodiments 1 -37, wherein the language sample is a dream report, a description of a picture, a thematic apperception test, or a neutral text reading. 39. The method of any one of embodiments 1 -38, wherein the language sample is obtained by passive acquisition. 40. The method of any one of embodiments 1 -39, wherein the language sample is a text sample. 41. The method of any one of embodiments 1 -40, wherein the language sample is an audio sample. 42. The method of embodiment 41, wherein the audio sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises one or more acoustic features. 43. The method of embodiment 42, wherein the one or more acoustic features are selected from the group consisting of a measure of irregular pitch, zero-crossing rate, kurtosis energy, harmonics-to-noise ratio (HNR), mel-frequency cepstral coefficients (MFCC), and frame energy. 44. The method of any one of embodiments 41 -43, wherein the audio sample is transcribed into text. 45. The method of any one of embodiments 1 -44, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of semantic coherence. 46. The method of embodiment 45, wherein a low measure of semantic coherence is positively correlated with the risk of developing psychosis. 47. The method of any one of embodiments 1 -46, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of syntactic complexity. 48. The method of embodiment 41, wherein a low measure of syntactic complexity is positively correlated with the risk of developing psychosis. 49. The method of any one of embodiments 1 -48, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of maximum phrase length. 50. The method of embodiment 49, wherein a low measure of maximum phrase length is positively correlated with the risk of developing psychosis. 51. The method of any one of embodiments 1 -50, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of lexicon breadth or depth. 52. The method of embodiment 51, wherein a high measure of lexicon breadth or depth is positively correlated with the risk of developing hypomania or mania and/or a low measure of lexicon breadth or depth is positively correlated with the risk of developing psychosis. 53. The method of any one of embodiments 1 -52, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of logorrhea. 54. The method of embodiment 53, wherein a high measure of logorrhea is positively correlated with the risk of developing hypomania or mania. 55. The method of any one of embodiments 1 -54, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of psychometrics. 56. The method of embodiment 55, wherein the measure of psychometrics is latent inhibition. 57. The method of embodiment 56, wherein a low measure of latent inhibition is positively correlated with the risk of developing psychosis, hypomania, or mania. 58. The method of any one of embodiments 1 -57, wherein the language sample is analysed to derive speech graph attributes. 59. The method of embodiment 58, wherein the speech graph attributes are input to a machine learning algorithm. 60. The method of any one of embodiments 1 -59, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of flight of thought. 61. The method of embodiment 60, wherein a high measure of flight of thought is positively correlated with the risk of developing hypomania or mania. 62. The method of any one of embodiments 1 -61, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of recursiveness. 63. The method of embodiment 62, wherein a high measure of recursiveness is positively correlated with the risk of developing hypomania or mania. 64. The method of any one of embodiments 1 -63, wherein the measure of risk is further based on one or more behavioural characteristics. 65. The method of embodiment 64, wherein the one or more behavioural characteristics are derived from a telephone record. 66. The method of embodiment 65, wherein the one or more behavioural characteristics derived from a telephone record comprise a number or frequency of outgoing calls or messages, a number or frequency of incoming calls or messages, a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages, a duration of one or more calls, a length of one or more messages, a number or frequency of newly added contacts, a number of changes in cell tower IDs, or a number of unique cell tower IDs. 67. The method of embodiment 66, wherein a number or frequency of outgoing calls or messages is positively correlated with the risk of developing hypomania or mania. 68. The method of embodiment 66 or 67, wherein a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages is positively correlated with the risk of developing hypomania or mania. 69. The method of any one of embodiments 66-68, wherein a duration of one or more calls is positively correlated with the risk of developing hypomania or mania. 70. The method of any one of embodiments 66-69, wherein the length of one or more messages is positively correlated with the risk of developing hypomania or mania. 71. The method of any one of embodiments 66-70, wherein a number of unique phone numbers is positively correlated with the risk of developing hypomania or mania. 72. The method of any one of embodiments 1 -71, wherein the one or more behavioural characteristics comprise a number or frequency of instances in which a mobile device screen is turned on. 73. The method of any one of embodiments 1 -72, wherein the one or more behavioural characteristics comprise a measure of activity detected by a sensor. 74. The method of embodiment 73, wherein the sensor is an antenna on a mobile device. 75. The method of embodiment 73 or 74, wherein the sensor is in communication with a global positioning system (GPS). 76. The method of any one of embodiments 73-75, wherein the measure of activity is a measure of mobility. 77. The method of embodiment 76, wherein a high measure of mobility is positively correlated with the risk of developing hypomania or mania. 78. The method of embodiment 73, wherein the sensor is an accelerometer. 79. The method of embodiment 78, wherein the measure of activity comprises a measure of movement. 80. The method of embodiment 79, wherein a measure of movement is positively correlated with the risk of developing hypomania or mania. 81. The method of embodiment 64, wherein the one or more behavioural characteristics are derived from a frequency, duration, or quality of sleep. 82. The measure of embodiment 81, wherein the measure of frequency, duration, or quality of sleep is derived from a frequency and/or duration of light exposure.
83. The method of embodiment 64, wherein the one or more behavioural characteristics are derived from:
(a) speed of typing: and/or
(b) one or more human-computer interactions selected from the group consisting of swipes, taps, and keystroke events.
84. The method of any one of embodiments 73-83, wherein the sensor is or is in communication with a wireless network hub. 85. The method of any one of embodiments 36-84, wherein the measure of risk is further based on a result of the EMA. 86. The method of embodiment 85, wherein the measure of risk refers to a risk or precipitating or exacerbating hypomania or mania, and wherein the EMA is a psychopathology questionnaire configured to assess hypomania or mania. 87. The method of embodiment 86, wherein the EMA is the Hypomania/Mania Symptom Checklist (HCL-32), the Clinician-Administered Rating Scale for Mania (CARS-M), the Young Mania Rating Scale (YMRS), or an equivalent variant thereof. 88. The method of embodiment 85, wherein the measure of risk refers to a risk of precipitating or exacerbating psychosis, and wherein the EMA is a psychopathology questionnaire configured to assess psychosis. 89. The method of embodiment 88, wherein the EMA is the psychosis screening questionnaire, the Schizophrenia Test and Early Psychosis Indicator (STEPI), the Cognitive Biases Questionnaire for psychosis (CBQp), or an equivalent variant thereof. 90. A method of characterizing the influence of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, on the perception of a patient administered therewith, the method comprising:
(i) obtaining a language sample from the patient;
(ii) providing one or more language characteristics of the language sample; and
(ii) based on the one or more language characteristics, determining a measure of psychedelic influence, wherein the measure of psychedelic influence correlates with the influence of the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, on the perception of the patient.
91. The method of embodiment 90, further comprising providing a notification based on the influence of 5-MeO- DMT, optionally the benzoate salt of 5-MeO-DMT, on the perception of the patient. 92. The method of embodiment 90 or 91, wherein 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, is administered on an in-patient basis. 93. The method of embodiment 92, wherein 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, is administered in a perceptible dose. 94. The method of embodiment 92 or 93, wherein 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, is administered on an outpatient basis. 95. The method of embodiment 94, wherein 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, is administered in a sub-perceptible dose. 96. The method of any one of embodiments 90-95, wherein the notification informs a clinician's decision when to release the patient from a supervised facility. 97. The method of any one of embodiments 90-96, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of semantic proximity to one or more concepts related to an influence of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT. 98. The method of embodiment 97, wherein a measure of semantic proximity to one or more facets related to an influence of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, is positively correlated with the influence of the therapy on the perception of the patient. 99. A method of screening a candidate for treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the method comprising:
(i) obtaining a behavioural sample from the candidate, wherein the candidate has not begun treatment;
(ii) deriving one or more behavioural characteristics from the behavioural sample; and
(iii) based on the one or more behavioural characteristics, determining a measure of risk, wherein the measure of risk correlates with a risk of precipitating or exacerbating psychosis, hypomania, or mania in the candidate.
100. The method of embodiment 99, further comprising sending a report to a third party. 101. The method of embodiment 100, wherein the third party is a clinical professional. 102. The method of embodiment 101, wherein the clinical professional is a physician, pharmacist, administrative professional, nurse, support professional, or caretaker. 103. The method of embodiment 100, wherein the third party is a computing platform. 104. The method of any one of embodiments 100-103, wherein the report informs a decision to prescribe or administer 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy. 105. The method of any one of embodiments 100-104, wherein the report informs a dosing regimen for the therapy. 106. A method of reducing a risk of developing psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO- DMT, the method comprising:
(i) obtaining a behavioural sample from the patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT;
(ii) deriving one or more characteristics of the behavioural sample;
(iii) based on the one or more characteristics, determining a measure of risk, wherein the measure of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and
(iv) based on the measure of risk, recommending whether to suspend the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT.
107. The method of embodiment 106, further comprising sending a report to a third party. 108. The method of embodiment 107, wherein the third party is a clinical professional. 109. The method of embodiment 108, wherein the clinical professional is a physician, pharmacist, administrative professional, nurse, support professional, or caretaker. 110. The method of embodiment 109, wherein the third party is a computing platform. 111. A method of assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the method comprising:
(i) providing a plurality of measures of risk, each measure of risk derived from one or more characteristics of a behavioural sample obtained from the patient, wherein each measure of risk is associated with a different treatment time point; and
(ii) comparing two or more of the plurality of measure of risk to obtain a differential measure of risk, wherein the patient is identified as at risk of precipitating or exacerbating psychosis, hypomania, or mania if the differential measure of risk exceeds a predetermined threshold. 112. The method of embodiment 111, further comprising sending one or more reports to a third party. 113. The method of embodiment 112, wherein the third party is a clinical professional. 114. The method of embodiment 113, wherein the clinical professional is a physician, pharmacist, administrative professional, nurse, support professional, or caretaker. 115. The method of embodiment 114, wherein the third party is a computing platform. 116. The method of any one of embodiments 112-115, wherein the one or more reports recommends suspending the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, if the differential risk measure exceeds the predetermined threshold. 117. A method of providing a regimen of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy to a patient, the method comprising:
(i) providing a differential measure of risk obtained by comparing two or more measures of risk, each measure of risk derived from one or more behavioural characteristics of a behavioural sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient, and wherein each measure of risk is associated with a different treatment time point; and
(ii) suspending the therapy if the differential measure of risk exceeds a predetermined threshold.
118. A method of administering 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, to a patient in need thereof, the method comprising:
(i) obtaining one or more measures of risk derived from one or more behavioural characteristics of a behavioural sample obtained from the patient, wherein the one or more measures of risk correlates with the risk of precipitating or exacerbating psychosis, hypomania, or mania in the patient; and
(ii) administering the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, if the measure of risk is below a predetermined threshold.
119. The method of any one of embodiments 99-118, further comprising, in response to determining that a candidate has a high measure of risk, prompting an EMA of the candidate. 120. The method of any one of embodiments 99-1 19, wherein the one or more behavioural characteristics are derived from a telephone record.
121. The method of embodiment 120, wherein the one or more behavioural characteristics derived from a telephone record comprise a number or frequency of outgoing calls or messages, a number or frequency of incoming calls or messages, a ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages, a duration of one or more calls, a length of one or more messages, a number or frequency of newly added contacts, a number of changes in cell tower IDs, or a number of unique cell tower IDs.
122. The method of embodiment 121, wherein the number or frequency of outgoing calls or messages is positively correlated with the risk of developing hypomania or mania. 123. The method of embodiment 121, wherein the ratio between a number or frequency of outgoing calls or messages and a number or frequency of incoming calls or messages is positively correlated with the risk of developing hypomania or mania. 124. The method of embodiment 121, wherein the duration of one or more calls is positively correlated with the risk of developing hypomania or mania. 125. The method of embodiment 121, wherein the length of one or more messages is positively correlated with the risk of developing hypomania or mania. 126. The method of embodiment 121, wherein a number of unique phone numbers is positively correlated with the risk of developing hypomania or mania. 127. The method of any one of embodiments 99-126, wherein the one or more behavioural characteristics comprise a number or frequency of instances in which a mobile device screen is turned on. 128. The method of any one of embodiments 99-127, wherein the one or more behavioural characteristics comprise a measure of activity detected by a sensor. 129. The method of embodiment 128, wherein the sensor is an antenna on a mobile device. 130. The method of embodiment 128 or 129, wherein the sensor is in communication with a global positioning system (GPS). 131. The method of any one of embodiments 128-130, wherein the measure of activity is a measure of mobility. 132. The method of embodiment 131, wherein a high measure of mobility is positively correlated with the risk of developing hypomania or mania. 133. The method of embodiment 128, wherein the sensor is an accelerometer. 134. The method of embodiment 133, wherein the measure of activity comprises a measure of movement. 135. The method of embodiment 134, wherein a measure of movement is positively correlated with the risk of developing hypomania or mania. 136. The method of any one of embodiments 129-135, wherein the sensor is or is in communication with a wireless network hub. 137. The method of any one of embodiments 99-136, wherein the measure of risk is further based on one or more language characteristics derived from a language sample. 138. The method of embodiment 137, wherein the language sample is elicited by a digital prompt, a questionnaire, or a clinician administered interview. 139. The method of embodiment 137 or 138, wherein the language sample is a dream report, a description of a picture, a thematic apperception test, or a neutral text reading. 140. The method of any one of embodiments 137-139, wherein the language sample is obtained by passive acquisition. 141. The method of any one of embodiments 137-140, wherein the language sample is a text sample. 142. The method of any one of embodiments 137-141, wherein the language sample is an audio sample. 143. The method of embodiment 142, wherein the audio sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises one or more acoustic features. 144. The method of embodiment 143, wherein the one or more acoustic features are selected from the group consisting of a measure of irregular pitch, zerocrossing rate, kurtosis energy, HNR, MFCC, and frame energy. 145. The method of any one of embodiments 142- 144, wherein the audio sample is transcribed into text. 146. The method of any one of embodiments 137-145, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of semantic coherence. 147. The method of embodiment 146, wherein a low measure of semantic coherence is positively correlated with the risk of developing psychosis. 148. The method of any one of embodiments 137-147, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of syntactic complexity. 149. The method of embodiment 148, wherein a low measure of syntactic complexity is positively correlated with the risk of developing psychosis. 150. The method of any one of embodiments 137-149, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of maximum phrase length. 151. The method of embodiment 150, wherein a high measure of maximum phrase length is positively correlated with the risk of developing hypomania or mania. 152. The method of any one of embodiments 137-151, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of lexicon breadth or depth. 153. The method of embodiment 152, wherein a high measure of lexicon breadth or depth is positively correlated with the risk of developing hypomania or mania. 154. The method of any one of embodiments 137-153, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of logorrhea. 155. The method of embodiment 154, wherein a high measure of logorrhea is positively correlated with the risk of developing hypomania or mania. 156. The method of any one of embodiments 137-155, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of psychometrics. 157. The method of embodiment 156, wherein the measure of psychometrics is latent inhibition. 158. The method of any one of embodiments 137-157, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of flight of thought. 159. The method of embodiment 158, wherein a high measure of flight of thought is positively correlated with the risk of developing hypomania or mania. 160. The method of any one of embodiments 137-159, wherein the language sample is analysed to derive the one or more language characteristics, wherein the one or more language characteristics comprises a measure of recursiveness. 161. The method of embodiment 160, wherein a high measure of recursiveness is positively correlated with the risk of developing hypomania or mania. 162. The method of any one of embodiments 119-161, wherein the measure of risk is further based on a result of the EMA. 163. The method of embodiment 162, wherein the measure of risk is a measure of risk of precipitating or exacerbating hypomania or mania, and wherein the EMA is a psychopathology questionnaire configured to assess hypomania or mania. 164. The method of embodiment 163, wherein the EMA is the Hypomania/Mania Symptom Checklist (HCL-32), the Clinician-Administered Rating Scale for Mania (CARS-M), the Young Mania Rating Scale (YMRS), or an equivalent variant thereof. 165. The method of embodiment 162, wherein the measure of risk is a measure of risk of precipitating or exacerbating psychosis, and wherein the EMA is a psychopathology questionnaire configured to assess psychosis. 166. The method of embodiment 165, wherein the EMA is the psychosis screening questionnaire, the STEPI, the CBQp, or an equivalent variant thereof. 167. The method of any one of embodiments 1 -166, wherein the measure of risk is determined using a machine learning algorithm. 168. The method of any one of embodiments 1 -167, wherein the measure of risk is determined using a cluster model. 169. The method of any one of embodiments 1 -168, wherein the measure of risk is determined based on a change of one or more of the characteristics relative to a reference characteristic. 170. The method of embodiment 169, wherein the reference characteristic is obtained from the patient at an earlier time point. 171. The method of embodiment 169, wherein the reference characteristic is a predetermined threshold. 172. The method of any one of embodiments 1 -171, wherein the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy is being administered for treatment of condition. 173. The method of embodiment 172, wherein the condition is a chronic condition. 174. The method of embodiment 172 or 173, wherein the condition is an inflammatory-related condition. 175. The method of any one of embodiments 172-174, wherein the condition is Alzheimer's disease. 176. The method of embodiment 172- 175, wherein the condition is depression. 177. The method of embodiment 176, wherein the depression is major depression, melancholic depression, or atypical depression. 178. The method of embodiment 176, wherein the depression is treatment-resistant depression. 179. The method of embodiment 176, wherein the depression is dysthymia. 180. The method of embodiment 172 or 173, wherein the condition is a psychological disorder selected from the group consisting of an anxiety disorder, an addiction, a compulsive behaviour disorder, or a symptom thereof. 181. The method of any one of embodiments 1 -171, wherein the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy is being administered for improvement of mood or enhancement of performance. 182. The method of any one of embodiments 1 -171, wherein the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy is being administered for treatment of stress, treatment of anxiety, treatment of addiction, treatment of depression, or treating of a compulsive behaviour. 183. The method of any one of embodiments 1 -171, wherein the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy is being administered for treatment to improve the mental well-being of a patient. 184. The method of any one of embodiments 1 -171, wherein the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy is being administered to reduce the risk of occurrence or reoccurrence of a psychopathology. 185. The method of any one of embodiments 1 -184, wherein the 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, therapy is part of a complex therapy, wherein the patient is additionally being treated with a psychotherapy. 186. The method of embodiment 185, wherein the psychotherapy comprises behavioural activation therapy, talk therapy, existential therapy, and/or self-actualization therapy. 187. The method of embodiment 186, wherein the behavioural activation therapy is brief behavioural activation for depression (BATD). 188. The method of any one of embodiments 185-187, wherein the complex therapy is provided to the patient in a specialized treatment facility. 189. The method of embodiment 172, wherein the condition is a neurodegenerative condition. 190. The method of embodiment 189, wherein the patient has undergone a cognitive assessment. 191. The method of embodiment 189, further comprising conducting a cognitive assessment on the patient. 192. The method of embodiment 190 or 191, further comprising discontinuing treatment based on a result of the cognitive assessment, wherein the negative result is associated with drug-related brain decline. 193. The method of embodiment 190 or 191, further comprising discontinuing treatment based on behavioural characteristic derived from an interaction between the patient and a device. 194. The method of any one of embodiments 193, wherein the cognitive assessment is selected from the group consisting of a mini-mental state examination (MMSE), Montreal cognitive assessment (MOCA), and Alzheimer's Disease assessment scale - cognitive subscale (ADAS-Cog). 195. A software program configured for assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, or a candidate for treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the software program comprising computer-readable instructions for performing the method of any one of embodiments 1 -194. 196. A software program configured for assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, or a candidate for treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the software program comprising computer-readable instructions for:
(i) obtaining one or more language and/or behavioural samples from the user;
(ii) deriving one or more language characteristics from the one or more language samples and/or one or more behavioural characteristics from the one or more behavioural samples; and based on the one or more language and/or behavioural characteristics, determining a measure of risk, wherein the measure of risk correlates with a risk of precipitating or exacerbating psychosis, hypomania, or mania in the candidate; and
(iii) reporting the measure of risk to the user and/or a third party.
197. The software program of embodiment 196, further comprising computer-readable instructions for receiving information regarding the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, wherein the information is selected from the group consisting of 5-MeO-DMT composition, a quantity of 5-MeO-DMT prescribed, a dosing schedule, a quantity of 5-MeO-DMT administered per dose, a frequency of doses administered, and a cumulative quantity of 5-MeO-DMT administered. 198. The software program of embodiment 197, wherein the computer-readable instructions for receiving information regarding the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, are configured to receive the information from the patient, a clinician, or the third party. 199. The software program of any one of embodiments 195-198, wherein the computer-readable instructions for receiving information regarding the treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMTare further configured to store and/or report the information regarding the treatment. 200. The software program of embodiment 199, wherein the computer-readable instructions for receiving information regarding the treatment are configured to report all or a portion of the information to the patient. 201. The software program of embodiment 200, wherein the computer-readable instructions for receiving information regarding the treatment are configured to report all or a portion of the information to the third party. 202. The software program of embodiment 201, wherein the computer-readable instructions for receiving information regarding the treatment are configured to report all or a portion of the information to the third party upon detecting non-compliance by the patient.
203. A computer system for assessing a risk of precipitating or exacerbating psychosis, hypomania, or mania in a patient undergoing treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT,or a candidate for treatment with 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, the computer system comprising:
(i) a mobile device comprising one or more input mechanisms, a processor, and one or more output mechanisms; and
(ii) a software program readable by the processor, the software program comprising instructions for:
(a) using the one or more input mechanisms, obtaining one or more language and/or behavioural samples from the user;
(b) using the processor, deriving one or more language characteristics from the one or more language samples and/or one or more behavioural characteristics from the one or more behavioural samples; and based on the one or more language and/or behavioural characteristics, determining a measure of risk, wherein the measure of risk correlates with a risk of precipitating or exacerbating psychosis, hypomania, or mania in the candidate; and
(c) using the one or more output mechanisms, reporting the measure of risk to the user and/or a third party.
204. The computer system of embodiment 203, wherein the software program further comprises computer- readable instructions for receiving information regarding the treatment wherein the information is selected from the group consisting of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, composition, a quantity of 5-MeO- DMT, optionally the benzoate salt of 5-MeO-DMT, prescribed, a dosing schedule, a quantity of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, administered per dose, a frequency of doses administered, and a cumulative quantity of 5-MeO-DMT, optionally the benzoate salt of 5-MeO-DMT, administered. 205. The computer system of embodiment 204, wherein the computer-readable instructions for receiving information regarding the treatment are configured to receive the information from the patient, a clinician, or the third party. 206. The computer system of any one of embodiments 203-205, wherein the computer-readable instructions for receiving information regarding the treatment are further configured to store and/or report the information regarding the treatment. 207. The computer system of embodiment 206, wherein the computer-readable instructions for receiving information regarding the treatment are configured to report all or a portion of the information to the patient. 208. The computer system of embodiment 207, wherein the computer-readable instructions for receiving information regarding the treatment are configured to report all or a portion of the information to the third party. 209. The computer system of embodiment 208, wherein the computer-readable instructions for receiving information regarding the treatment are configured to report all or a portion of the information to the third party upon detecting non-compliance by the patient. 210. The software program of any one of embodimentsl95 -202 or the computer system of any one of embodiments 203-209, further comprising a psychotherapy application, wherein the psychotherapy application is configured to provide psychotherapy to the patient or candidate. 211. The software program or computer system of embodiment 210, wherein the psychotherapy is provided via telemedicine. 212. The software program or computer system of embodiment 210 or 211, wherein the psychotherapy is behavioural activation therapy.
In an aspect there is provided 5-MeO-DMT benzoate for use in a method of treatment of a psychiatric or neurological disorder, the method comprising administering a dose of 5-MeO-DMT benzoate to a patient in need thereof, wherein the brain activity of the patient is monitored using electroencephalography (EEG). Advantageously, 5-MeO- DMT is administered alongside monitoring of brain activity to determine peak psychedelic experience.
In an embodiment, EEG is monitored to indicate the onset or presence of ego-dissolution or altered consciousness. In an embodiment, wherein the onset or presence of ego-dissolution or altered consciousness is characterised by a characteristic EEG pattern. In an embodiment, the characteristic EEG pattern is pathognomonic and/or indicative of a 5-MeO-DMT therapeutic response. In an embodiment, the EEG pattern is selected from one or more of: locationspecific (e.g. prefrontal, and frontal) alterations; decreases in total spectral power in alpha and/or beta bands; marked increases in spontaneous signal diversity; emergence of theta and/or delta oscillations. In an embodiment, a subsequent dose of 5-MeO-DMT benzoate is administered to the patient, in the case where the onset or presence of ego-dissolution or altered consciousness is not indicated by the EEG in an assessment window following a prior dose of 5-MeO-DMT benzoate. In an embodiment, a subsequent dose of 5-MeO-DMT benzoate is not administered to the patient, in the case where the onset or presence of ego-dissolution or altered consciousness is indicated by the EEG in an assessment window, following a prior dose of 5-MeO-DMT benzoate. In an embodiment, a subsequent dose of 5-MeO-DMT benzoate is administered to the patient, in the case where the ending of ego-dissolution or altered consciousness is indicated by the EEG in an assessment window following a prior dose of 5-MeO-DMT benzoate. In an embodiment, a subsequent dose of 5-MeO-DMT benzoate is not administered to the patient, in the case where a session assessment window has expired following a prior, or first, dose of 5-MeO-DMT benzoate. In an embodiment, the monitored brain activity of the patient is assessed with reference to a database of EEG measurements taken from patients undergoing, and/or who have undergone, 5-MeO-DMT benzoate therapy.
In an embodiment, the 5-MeO-DMT benzoate is administered via an intranasal route. In an embodiment, the 5- MeO-DMT benzoate is administered via a transdermal route via a microneedle patch, or a transdermal patch pump. In an embodiment, the microneedle patch is removed, or the patch pump infusion is stopped, in the case where the onset or presence of ego-dissolution or altered consciousness is indicated by the EEG in an assessment window. In an embodiment, the dose or dosages of 5-MeO-DMT benzoate is administered via a continuous s/c infusion or a transdermal patch pump. In an embodiment, the dose or dosages of 5-MeO-DMT benzoate is administered so as to maintain a state of ego-dissolution or altered consciousness for a desired time window of time. In an embodiment, prior to administration of the 5-MeO-DMT benzoate to the patient, the patient takes part in a dose finding screening exercise, wherein the brain activity of the patient is monitored using EEG during the administration of increasing dosages of 5-MeO-DMT benzoate, in order to select a suitable treatment dose.
In an embodiment, the patient is monitored using an electroencephalography (EEG) headset which is connected to a app, smart phone device, tablet, computer device, or equivalent device, and in the case where the onset or presence of ego-dissolution or altered consciousness is indicated, a visual and/or audible alert is generated by the app, smart phone device, tablet, computer device, or equivalent device. In an embodiment, the headset is connected to the app, smart phone device, tablet, computer device, or equivalent device via a wireless connection, e.g. via Bluetooth®. In an embodiment, the patient is monitored using an electroencephalography (EEG) headset and when the onset or presence of ego-dissolution or altered consciousness is indicated, a visual and/or audible alert is generated by the headset. In an embodiment, the brain activity (e.g. EEG data), of the patient is monitored by a computer algorithm. In an embodiment, the onset of or presence ego-dissolution or altered consciousness is determined by the computer algorithm or is determined together with the authority of a supervising healthcare professional (HCP).
In an embodiment, the treatment takes place in a dedicated therapy space in the presence of a supervising healthcare professional (HCP). In an embodiment, the supervising HCP and the patient engage in psychotherapy, optionally such therapy is initiated following the indication that ego-dissolution is imminent, is occurring or has occurred. In an embodiment, the 5-MeO-DMT benzoate may be any salt of 5-MeO-DMT such as the chloride salt, or may be the freebase of 5-MeO-DMT.
In an embodiment, there is provided the use of 5-MeO-DMT benzoate in a method of treatment of a psychiatric or neurological disorder, the method comprising administering 5-MeO-DMT benzoate to a patient in need thereof, wherein the brain activity of the patient is monitored using electroencephalography (EEG) to determine whether or not ego-dissolution occurs, wherein this state of altered consciousness is characterised by a specific EEG pattern pathognomonic for the 5-MeO-DMT induced changes sufficient to elicit a therapeutic response, said EEG pattern comprises location-specific (prefrontal, and frontal) alterations which optionally may be marked decreases in total spectral power in alpha and beta bands, marked increases in spontaneous signal diversity and the emergence of theta and delta oscillations.
In an embodiment, the brain activity of the patient is monitored constantly. In an embodiment, 'ego-dissolution' is used interchangeably with 'ego death', 'a complete loss of subjective self-identity', 'psychic death', 'mystical experience', 'peak psychedelic experience', 'peak psychedelic intensity', 'ego-loss' and/or 'complete transcendence of self'. In an embodiment, there is provided the use of 5-MeO-DMT benzoate in a method of treatment, wherein following administration of 5-MeO-DMT benzoate and after the passage of a predetermined length of time, if egodissolution has been deemed not to have occurred, the patient is administered a second dose of 5-MeO-DMT benzoate.
In an embodiment, the second dose is a higher dose. In an embodiment, the second dose is a lower dose. In an embodiment, there is provided the use of 5-MeO-DMT benzoate in a method of treatment, wherein following administration of 5-MeO-DMT benzoate and after the passage of a predetermined length of time, if ego-dissolution has been deemed not to have occurred, the patient is not administered a further dose of 5-MeO-DMT benzoate. In an embodiment, the predetermined length of time depends on the exact formulation of 5-MeO-DMT benzoate administered to the patient and the route of said administration.
In embodiment, the predetermined length of time is 1 to 60 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 5 to 30 minutes, 5 to 25 minutes, 5 to 20 minutes, 5 to 15 minutes, 5 to 10 minutes, 10 to 30 minutes or 10 to 20 minutes. In an embodiment, administration of 5-MeO-DMT benzoate is halted when ego-dissolution is determined to have occurred. In an embodiment, the patient is kept in a state of ego-dissolution for 1 to 60 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 5 to 30 minutes, 5 to 25 minutes, 5 to 20 minutes, 5 to 15 minutes, 5 to 10 minutes, 10 to 30 minutes or 10 to 20 minutes. In an embodiment, the patient is kept in a state of egodissolution for a length of time which is individual to the patient. In an embodiment, the brain activity of the patient is compared against a reference database containing EEG measurements of the patient undergoing 5-MeO-DMT benzoate therapy previously. In an embodiment, the brain activity of the patient is compared against a reference database containing EEG measurements of other patients undergoing 5-MeO-DMT benzoate therapy previously.
In an embodiment, the brain activity of the patient is compared against both a reference database containing EEG measurements of patients receiving 5-MeO-DMT benzoate therapy and a reference database containing EEG measurements of the patient receiving 5-MeO-DMT therapy previously. In an embodiment, the 5-MeO-DMT benzoate is administered via any delivery route previously or subsequently described. In an embodiment, the 5- MeO-DMT benzoate is administered via the intranasal route. In an embodiment, the 5-MeO-DMT benzoate is administered via a microneedle patch, or a transdermal patch pump. In an embodiment, when ego-dissolution is determined to have occurred the administration of the 5-MeO-DMT benzoate is stopped. In an embodiment, when ego-dissolution is determined to have occurred the microneedle patch is removed, or the patch pump infusion is stopped.
In an embodiment, when the 5-MeO-DMT benzoate is administered via a continuous s/c infusion or a transdermal patch pump, the infusion pump or the transdermal patch pump is connected to the EEG device and the levels of 5- MeO-DMT administered are controlled such that the patient is kept in a state of ego-dissolution for a desired length of time. In an embodiment, this length of time is about I to 60 minutes, about 1 to 50 minutes, about 1 to 40 minutes, about 1 to 30 minutes, about 1 to 20 minutes about 1 to 10 minutes or about 1 to 5 minutes.
In an embodiment, this length of time is about 50 to 60 minutes, about 40 to 60 minutes, about 30 to 60 minutes, about 20 to 60 minutes or about 10 to 60 minutes. In an embodiment, prior to administration of the 5-MeO-DMT benzoate to the patient, the patient has taken part in a dose finding screening exercise wherein the brain activity of the patient has been monitored during the administration of increasing dosages of 5-MeO-DMT in order to select an appropriate treatment dose. In an embodiment, the patient is monitored using an electroencephalography (EEG) headset which is connected to a smart phone device and when ego-dissolution is determined to occur a visual and/or audible alert is generated by the smart phone device. In an embodiment, the patient is monitored using an electroencephalography (EEG) headset which is connected to a computer device and when ego-dissolution is determined to occur a visual and/or audible alert is generated by the computer device.
In an embodiment, the patient is monitored using an electroencephalography (EEG) headset and when egodissolution is determined to occur a visual and/or audible alert is generated by the headset. In an embodiment, the headset and smart phone device or computer device are connected via Bluetooth. In an embodiment, the brain activity of the patient, as represented by EEG measurements, is monitored by a computer algorithm. In an embodiment, the determination of whether ego-dissolution has occurred is made by a computer algorithm.
In an embodiment, the 5-MeO-DMT benzoate is crystalline. In an embodiment, the 5-MeO-DMT benzoate is crystalline and characterised as described previously or subsequently. In an embodiment, the 5-MeO-DMT benzoate is replaced with the HCI salt. In an embodiment, the patients EEG is monitored and analysed by a statistical analysis and/or machine learning algorithm, Statistical analyses and/or machine learning algorithm(s) can be characterized by a learning style including any one or more of: supervised learning (e.g., using back propagation neural networks), unsupervised learning (e.g., K-means clustering), semi-supervised learning, reinforcement learning (e.g., using a Q- learning algorithm, using temporal difference learning, etc.), and any other suitable learning style.
Furthermore, any algorithm(s) can implement any one or more of: a regression algorithm, an instance-based method (e.g., k-nearest neighbor, learning vector quantization, self-organizing map, etc.), a regularization method, a decision tree learning method (e.g., classification and regression tree, chi-squared approach, random forest approach, multivariate adaptive approach, gradient boosting machine approach, etc.), a Bayesian method (e.g., naive Bayes, Bayesian belief network, etc.), a kernel method (e.g., a support vector machine, a linear discriminate analysis, etc.), a clustering method (e.g., k-means clustering), an associated rule learning algorithm (e.g., an Apriori algorithm), an artificial neural network model (e.g., a back-propagation method, a Hopfield network method, a learning vector quantization method, etc.), a deep learning algorithm (e.g., a Boltzmann machine, a convolution network method, a stacked auto-encoder method, etc.), a dimensionality reduction method (e.g., principal component analysis, partial least squares regression, etc.), an ensemble method (e.g., boosting, boot strapped aggregation, gradient boosting machine approach, etc.), and any suitable form of algorithm.
It is believed that in order for psychedelic therapies to be efficacious they need to alter the consciousness to such an extent that patients describe "mystical experiences" or a state of "ego dissolution". There is a clear correlation between the dose of the psychedelic drug and this state of ego dissolution and the resulting psychiatric efficacy, but individual variation and the fact that patients are not fully able to report their experience while they are under the influence of the psychedelic treatment make it difficult for the healthcare provider to judge if the right therapeutic dose has been applied. Since psychedelic drugs alter the brain waves and these alterations can be detected using electroencephalographic recordings, we describe a method to reliably detect a 5-MeO-DMT benzoate induced ego dissolution state exactly at the moment it occurs using a specific EEG algorithm. The timely knowledge of this occurrence enables the treating healthcare provider to make rapid dose adjustments which will optimize the outcome of the therapeutic session. Drug concentrations can be raised until a sufficient psychedelic response is elicited, or the drug adsorption could be stopped when the right drug levels are reached. Patients who did not respond to a specific dose of 5-MeO-DMT, whose EEG indicates that the ego-dissolution did not occur may benefit from re-treatment with a higher dose. Patients who did not respond to treatment wherein ego-dissolution did occur, likely will not benefit from re-treatment.
In an embodiment, there is provided the use of 5-MeO-DMT benzoate in a method of treatment of a psychiatric or neurological disorder, the method comprising administering a dose of 5-MeO-DMT benzoate to a patient in need thereof, wherein the brain activity of the patient is monitored using electroencephalography (EEG) and wherein the 5-MeO-DMT is administered via the transdermal route.
Example 47: MDMA Synthesis
There are numerous routes available to synthesise MDMA via a variety of different intermediates. In the original patent for Merck, safrole is brominated to l-(3,4-methylenedioxyphenyl)-2-bromopropane and then reacted with methylamine. It is possible to isomerise safrole to isosafrole in the presence of strong base, and then oxidise isosafrole to MDP2P (3,4-methylenedioxyphenyl-2-propanone). Another option is to use the Wacker process to oxidise safrole directly to MDP2P with a palladium catalyst. Once MDP2P has been prepared, a reductive amination produces a racemic MDMA (equal parts (R) and (S) MDMA). Figure 122 shows a summary of the synthetic route to prepare MDMA from piperonal. Figure 123 shows a summary of the synthetic route to prepare MDMA (and related analogues) from safrole.
Example 48: Transdermal Delivery
Approach 1
In an aspect, there is provided a microneedle array comprising a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable polymer composition, wherein the microneedle array further comprises 5-MeO-DMT.
In an embodiment, the microneedle array further comprises an empathogen/entactogen, such as MDMA.
In an embodiment, there is provided a method of treatment wherein the pharmaceutical combination is administered via the transdermal route. In an embodiment there is provided a microneedle array for use in administration of the pharmaceutical combination, wherein said array comprises a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable composition. In an embodiment, there is provided a microneedle array comprising a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable polymer composition, characterised in that the microneedle array further comprises an empathogen/entactogen such as MDMA. In an embodiment, there is provided a microneedle array for use in administration of the pharmaceutical combination, wherein said array comprises a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable hydrogel forming polymer composition. In an embodiment, there is provided a microneedle array comprising a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable hydrogel polymer composition, characterised in that the microneedle array further comprises an empathogen/entactogen, such as MDMA, and 5-MeO-DMT.
In an embodiment, the empathogen/entactogen such as MDMA is coated on the outside of the tip of the microneedle/and or comprised within the polymer composition of the tip of the microneedle. In an embodiment, the empathogen/entactogen such as MDMA is coated on the outside of the very tip of the microneedle/and or comprised within the polymer composition of the tip of the microneedle. In an embodiment, the 5-MeO-DMT is comprised within the polymer composition of the microneedle array. In an embodiment, the microneedle array further comprises a reservoir or matrix comprising 5-MeO-DMT or the microneedle array is in communication with a reservoir or matrix comprising 5-MeO-DMT. In an embodiment, the 5-MeO-DMT is the benzoate salt. In an embodiment, it is the crystalline benzoate salt. In an embodiment, the swellable polymer composition is a swellable hydrogel forming polymer composition. In an embodiment, the microneedles of the array comprise one or more hydrogel-forming polymers containing one or more hydrophilic functional groups, such as polyvinylalcohol, amylopectin, carboxymethylcellulose (CMC)chitosan, poly(hydroxyethylmethacrylate) (polyHEMA), poly(acrylic acid), and poly(caprolactone), ora Gantrez ® -type polymer. In an embodiment, the microneedles comprise a Gantrez ® -type polymer. In an embodiment, the Gantrez ® -type polymer is the polymer as made available as of 1 January 2021.
In an embodiment, the polymer composition of the microneedles is cross-linked. In an embodiment, the polymer composition of the base element is cross-linked. In an embodiment, the polymer composition of the microneedles and/or the base element are cross-linked. In an embodiment, the cross-linking is physical or chemical or a combination of both. In an embodiment, the swellable hydrogel forming polymer composition is a Gantrez ® -type polymer cross-linked using a polyhydric alcohol. In an embodiment, the microneedles of the microneedle array are l-3000pm in height. In an embodiment, the microneedles of the microneedle array have a width (or, in the case of microneedles with substantially circular cross sections, a diameter) of 50 - 500 pm. In an embodiment, the base element and the microneedles are comprised of the same material. In an embodiment, the base element and the microneedles are comprised of different materials. In an embodiment, the empathogen/entactogen of the microneedle array is MDMA. In an embodiment, there is provided a transdermal delivery device comprising a microneedle array. In an embodiment, the movement of 5-MeO-DMT benzoate from the microneedle array into the skin is controlled iontopherically. In an embodiment, the movement of the empathogen/entactogen such as MDMA from the microneedle array into the skin is controlled iontopherically. In an embodiment, the transdermal delivery device is for use in a method of treatment. In an embodiment, the method of treatment is a method of treatment of depression. In an embodiment, the method of treatment is a method of treatment of treatment-resistant depression.
In an embodiment, the method of treatment comprises the steps of: inducing a positive psychological state in a patient by administering the entactogen/empathogen, such as MDMA, component to the patient; and administering the 5-MeO-DMT component to the patient.
In an embodiment, the entactogen/empathogen, such as MDMA, component is administered to the patient prior the administration of 5-MeO-DMT to the patient.
In an embodiment, the method of treatment comprises the steps of: inducing a positive psychological state in a patient by administering MDMA to the patient; and administering 5-MeO-DMT benzoate to the patient.
In an embodiment, the dosages of the various components of the various transdermal delivery approaches may be as described previously or subsequently. In an embodiment, the MDMA may be a salt form. In an embodiment, the MDMA may be the hydrochloride salt. In an embodiment, any references to the benzoate salt of 5-MeO-DMT may be considered to be references to the hydrochloride salt. Any hydrogel polymer composition which can penetrate the stratum corneum of skin and which swells in the presence of liquid may be used. In an embodiment, the microneedles are fabricated from one or more hydrogel-forming polymers containing one or more hydrophilic functional groups. Examples of suitable polymers include, but are not necessarily limited to, polyvinylalcohol), amylopectin, carboxymethylcellulose (CMC)chitosan, poly(hydroxyethylmethacrylate) (polyHEMA), poly(acrylic acid), and poly(caprolactone), or a Gantrez ® -type polymer. Gantrez ® -type polymers include poly(methylvinylether/maleic acid), esters thereof and similar, related, polymers (eg poly(methyl/vinyl ether/maleic anhydride). In a particular embodiment of the invention, the hydrogel-forming polymer is a Gantrez ® -type polymer such as poly(methyl/vinyl ether/maleic acid) (PMVEMA), an ester thereof or poly(methyl/vinyl ether/maleic anhydride) (PMVEMAH).
Crosslinking of polymers may be used to further vary the strength and swelling characteristics of microneedles as well as the release characteristics of the microneedles. For example a lightly-crosslinked hydrogel microneedle could rapidly deliver a drug bolus where one dose only is required e.g. for vaccine delivery. Optionally, a moderately- crosslinked hydrogel microneedle could be used to allow prolonged drug delivery, thus facilitating a constant drug plasma level. Optionally moderately-crosslinked hydrogel microneedles could keep puncture holes in the SC open. Indeed, moderately-crosslinked hydrogel microneedles might optionally widen the puncture holes as a result of absorption of moisture from tissue, and swelling of the microneedles. The polymer composition of the microneedles and/or the base element may be cross-linked using any suitable technique known in the art. The crosslinking may be physical or chemical or a combination of both. Suitable cross-linking agents include polyhydric alcohols (eg glycerol, propylene glycol (poly(ethylene glycol) or a polyamino compound which can form amides with reactive groups of a polymer. In one embodiment, of the invention, the hydrogel-forming polymer is a Gantrez ® type polymer cross-linked using a polyhydric alcohol. The microneedles of the microneedle arrays of the invention may be of any size and shape such that they can penetrate the stratum corneum of mammalian skin without breaking upon their insertion into the skin. In one embodiment, the microneedles of the microneedle arrays of the invention are 1 - 3000 pm in height. In one embodiment, the microneedles have a width (or, in the case of microneedles with substantially circular cross sections, a diameter) of 50 - 500 pm. The base element and microneedles may be comprised of the same or different materials. Typically the base element will be composed of the same polymer composition as the microneedles. The mechanical strength and rate of swelling of the microneedles of the microneedle arrays of the invention will be determined by a number of factors including the shape of the microneedles and the polymer(s) of which the microneedles are composed.
In an embodiment, there is provided a transdermal delivery device comprising a microneedle array as previously or subsequently described. In such transdermal delivery devices, the 5-MeO-DMT benzoate may be comprised within a reservoir or matrix with which the microneedle array is in communication. In use, on insertion of the microneedle array into skin, the 5-MeO-DMT benzoate moves from the reservoir or matrix through the microneedles to the skin. In such an embodiment, the empathogen/entactogen such as MDMA is coated on the outside of the very tip of the microneedle and/or comprised within the polymer composition of the tip of the microneedle, such that delivery of the empathogen/entactogen such as MDMA is initiated almost immediately.
Additionally or alternatively, the 5-MeO-DMT benzoate may be comprised within the polymer composition of the microneedle array. In such an embodiment, the empathogen/entactogen such as MDMA is coated on the outside of the very tip of the microneedle and/or comprised within the polymer composition of the tip of the microneedle, such that delivery of the empathogen/entactogen such as MDMA is initiated almost immediately. This has the distinct advantage over conventional microneedle arrays in which drugs are delivered via a channel in the microneedle that, on insertion into the skin, drug delivery may be initiated almost immediately.
In particular embodiments, 5-MeO-DMT benzoate can be chemically bonded to the polymer(s) making up the microneedles and/or base elements. In this case, the 5-MeO-DMT benzoate can be released upon insertion into the skin by; dissolution of the microneedles, hydrolysis, enzymatic or spontaneous non-catalysed breakage of the bonds holding it to the polymer(s). The rate of drug release can thus be determined by the rate of reaction/bond breakage. In particular embodiments, the empathogen/entactogen such as MDMA can be chemically bonded to the polymer(s) making up the microneedles and/or base elements. In this case, the empathogen/entactogen such as MDMA can be released upon insertion into the skin by; dissolution of the microneedles, hydrolysis, enzymatic or spontaneous noncatalysed breakage of the bonds holding it to the polymer(s). The rate of drug release can thus be determined by the rate of reaction/bond breakage.
In embodiments of the transdermal delivery device of the invention, movement of 5-MeO-DMT benzoate from the microneedle array into the skin may occur passively. Alternatively, movement may be controlled externally, for example iontophoretically. In embodiments of the transdermal delivery device of the invention, movement of the empathogen/entactogen such as MDMA from the microneedle array into the skin may occur passively. Alternatively, movement may be controlled externally, for example iontophoretically. In an embodiment, there is provided an iontophoretic device comprising a microneedle array as previously or subsequently described. In an embodiment, there is provided a method of delivering 5-MeO-DMT benzoate and an empathogen/entactogen such as MDMA through or into the skin comprising:
- providing a microneedle array or a transdermal therapeutic device, either of which may be as previously or subsequently described, wherein the microneedle array or transdermal therapeutic device comprises 5- MeO-DMT benzoate and an empathogen/entactogen such as MDMA,
- applying the microneedle array to the skin such that the microneedles protrude through or into the stratum corneum,
- allowing the microneedles to swell,
- allowing the 5-MeO-DMT benzoate and the empathogen/entactogen such as MDMA to flow through the microprotusions into the skin.
Transdermal delivery devices can be affixed to the skin or other tissue to deliver 5-MeO-DMT benzoate and the empathogen/entactogen such as MDMA continuously or intermittently, for example for durations ranging from a few seconds to several hours or days. Arrays of microneedles having different characteristics from each other, for example having different shapes, polymer compositions, crosslinkers or degrees of crosslinking, thus enabling a single microneedle array to have regions which can deliver drugs at different rates. This would enable, for example, a rapid bolus to be delivered to a patient on positioning of the microneedle array followed by a slower sustained release of the same active agent. Indeed, the microneedle arrays of the invention may be used to deliver more than one active agent from the same transdermal therapeutic device. For example, a first active agent could be comprised within the polymer of which the microneedles are composed with a second active agent stored in a reservoir. On positioning on the skin and puncturing of the stratum corneum, the microneedles will swell and the active agent will be released from the microneedles. Subsequently, the second active agent may be released from the reservoir and enter the skin via the microneedles.
Drug contained in the microneedles themselves will be rapidly released upon swelling, initially as a burst release due to drug at the surface of the microneedles. The subsequent extent of release will be determined by crosslink density and the physicochemical properties of the drug. Release of drug from the drug reservoir will occur more slowly at first as a result of the time required to swell the microneedles up as far as the drug reservoir, subsequent partitioning of the drug into the swollen microneedles and diffusion of the drug through the swollen matrix. The microarrays may thus be adapted to deliver two active agents in succession, with the composition adapted, e.g. by crosslinking of the composition of the microneedles, to vary delivery times of one or both active agents.
In an embodiment, there is provided a microneedle array for use in the administration of 5-MeO-DMT benzoate and an empathogen/entactogen such as MDMA, wherein said array comprises a plurality of microneedles composed of a swellable polymer composition which in its dry state is hard and brittle to penetrate the stratum corneum of a patients skin, wherein the microneedles are fabricated from at least one polymer selected from poly(methylvinylether/maleic acid), esters thereof and poly (methyl/vinyl ether/maleic anhydride), wherein the polymer is a cross-linked polymer, and using a cross-linker at a polymer-crosslinker ratio of 2:1. In an embodiment, there is provided a transdermal delivery device capable of the administration of two different active agents with different release profiles. The first active agent is delivered rapidly over less than 5, less than 10 or less than 15 minutes. The second active agent is delivered only after the rapid delivery of the first active agent.
In an embodiment, the first active agent is, for example, coated on the outer service of each of a plurality of microneedles whilst the second active agent is, for example, localised on an inner layer of each of a plurality of microneedles. In an embodiment, the outer surface of each microneedle is dissolvable. In an embodiment, the inner layer(s) of each microneedle comprise a swellable polymer mix, such as a hydrogel. In an embodiment, the first active agent is coated on and/or localised on an inner layer of the tip of each microneedle. In an embodiment, the second active agent is localised on an inner layer of the remainder of each microneedle. In an embodiment, the tip of each microneedle dissolves rapidly upon application to a patient/activation to release the first active agent rapidly. In an embodiment, the second active agent is released following the rapid release of the first.
In an embodiment, there is provided a transdermal delivery device comprising a plurality of a first type of microneedle and a plurality of a second type of microneedle. In an embodiment, the first type of microneedle is a rapidly dissolvable microneedle. In an embodiment, the outer surface and/or the inner layer(s) of each of the first type of microneedle are coated with/have localised therein a first active agent. In an embodiment, the second type of microneedle is a microneedle comprising a swellable polymer composition. In an embodiment, the second type of microneedle comprising a second active agent. In an embodiment, the first active agent is, for example, an entactogen/empathogen such as MDMA and the second active agent is a psychedelic, such as 5-MeO-DMT benzoate.
Approach 2
In an embodiment, there is provided a pharmaceutical combination for use in a method of treatment wherein said combination is administered via the transdermal route. In an embodiment, said combination is administered via a patch or array comprising microneedles. In an embodiment, said combination is administered via a patch pump. In an embodiment, a plurality of the needles of the microneedle patch/array are coated with 5-MeO-DMT benzoate and a plurality of the needles are coated with an empathogen/entactogen such as MDMA. In an embodiment, the microneedle patch is configured such that release of 5-MeO-DMT benzoate only occurs following release of the empathogen/entactogen such as MDMA. In an embodiment, about 10% to 80% of the length of each needle is coated with either 5-MeO-DMT benzoate or an empathogen/entactogen such as MDMA. In an embodiment, at least 95% of the empathogen/entactogen such as MDMA is released from the microneedle patch within 20 minutes of application of said patch. In an embodiment, at least a % of the empathogen/entactogen such as MDMA sufficient for a therapeutic effect is released from the microneedle patch within 20 minutes of application of said patch. In an embodiment, at least 95% of the 5-MeO-DMT benzoate is released from the microneedle patch within 2 hours of application of said patch. In an embodiment, the transdermal patch pump is configured to release the 5-MeO-DMT benzoate only after release of the empathogen/entactogen such as MDMA.
In an embodiment, the transdermal patch pump is configured to release the 5-MeO-DMT benzoate 1-3 hours following release of the empathogen/entactogen such as MDMA. In an embodiment, the transdermal patch pump is configured to release the 5-MeO-DMT benzoate 1-2 hours following release of the empathogen/entactogen such as MDMA. In an embodiment, the transdermal patch pump is configured to release the 5-MeO-DMT benzoate 0.5- 3 hours following release of the empathogen/entactogen such as MDMA. In an embodiment, there is provided a transdermal patch pump as described previously or subsequently. In an embodiment, there is provided a microneedle patch as described previously or subsequently.
In an embodiment, there is provided an intracutaneous delivery system, comprising a plurality of microneedles having a formulation coated thereon covering about 10% to 80% of the length of each microneedle measured from the tip to the base, wherein the coating comprises either a therapeutically effective amount of an empathogen/entactogen such as MDMA or a therapeutically effective amount of 5-MeO-DMT benzoate, said delivery system configured such that at least 95% of the empathogen/entactogen is released from the system to the stratum corneum of a human patient prior to release of 5-MeO-DMT benzoate from the system.
In an embodiment, the transdermal patch pump, microneedle patch or intracutaneous delivery system comprises an array of about 1 cm2 to about 20 cm2, of about 1 cm2 to about 10 cm2, of about 1 cm2 to about 7.5 cm2, of about 1 cm2 to about 6 cm2, of about 2 cm2 to about 6 cm2 or about 3 cm2 to about 6 cm2. In an embodiment, the array has a density of about 100 to about 3000 microneedles/cm2, of about 100 to about 2000 microneedles/cm2, of about 100 to about 1000 microneedles/cm2, of about 200 to about 2000 microneedles/cm2 or about 200 to 1000 microneedles/cm2.
In an embodiment, the microneedles have a width of about 10 to about 500 micrometres, of about 10 to about 1000 micrometres, of about 10 to about 1500 micrometres, of about 10 to 400 micrometres, or about 10 to 300 micrometres, of about 10 to about 200 micrometres or about 10 to about 100 micrometres. In an embodiment, the microneedles have a tip angle of about 30 to about 70 degrees, of about 20 to about 80 degrees, of about 30 to about 60 degrees or of about 30 to about 50 degrees. In an embodiment, the transdermal patch pump, microneedle patch or intracutaneous delivery system are stable at room temperature for at least 12 months. In an embodiment, they are stable for at least 6 months.
Approach 3
In an embodiment, there is provided a transdermal patch pump that administers 5-MeO-DMT benzoate in solution over time with a defined injection rate. In an embodiment, there is provided a transdermal patch pump comprising an array of microneedles for rapid delivery of an entactogen/empathogen such as MDMA and a needle for delivery of 5-MeO-DMT benzoate. In an embodiment, the microneedles are as previously or subsequently described. In an embodiment, the entactogen/empathogen such as MDMA is administered as soon as the pump patch is applied to the patient. In an embodiment, the entactogen/empathogen such as MDMA is administered following interaction of the patient or another person with the pump patch. In an embodiment, the patch pump administers the entactogen/empathogen such as MDMA prior to administration of 5-MeO-DMT benzoate. In an embodiment, the 5-MeO-DMT benzoate is administered from the patch pump 5, 10, 15 or 20 minutes after administration of the entactogen/empathogen such as MDMA. In an embodiment, the 5- MeO-DMT benzoate is administered from the patch pump over 5-20, 10-20 or 15-20 minutes, after administration of the entactogen/empathogen such as MDMA. In an embodiment, there is provided a transdermal patch pump comprising two different active agents, an entactogen/empathogen such as MDMA and a psychedelic such as 5- MeO-DMT benzoate. In an embodiment, one of the active agents is administered prior to administration of the other. In an embodiment, one of the active agents is administered over 5, 10, 15 or 20 minutes. In an embodiment, one of the active agents is administered over 5-20, 10-20 or 15-20 minutes.
In an embodiment, the 5-MeO-DMT benzoate is crystalline, as described previously or subsequently. In an embodiment, the 5-MeO-DMT is the hydrochloride salt rather than the benzoate salt. In an embodiment, the hydrochloride is crystalline, as described previously or subsequently.
In an embodiment, there is provided a microneedle array (1) comprising comprising a base element (2) and a plurality of microneedles (3) which project from said base element, wherein the microneedles are composed of a swellable polymer composition. In an embodiment, a tip (4) of a microneedle comprises an entactogen/empathogen such as MDMA. Figure 133 shows one embodiment of a microneedle array (1).
Example 49: X-Ray Powder Diffractoaram (XRPD) Analysis of 5-MeO-DMT hydrochloride
XRPD analysis of two lots of 5-MeO-DMT hydrochloride (lot 20/20/126-FP and lot 20/45/006-FP) was performed, both were of_well-ordered material with moderate relative crystallinity and exhibited the same crystalline pattern, which can be seen in Figures 105-107. In the absence of any other known sample label, the pattern was assigned as 5-MeO-DMT Hydrochloride Pattern A. In one embodiment, there is provided crystalline 5-MeO-DMT hydrochloride, characterised by peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°20±O.1°20 as measured by x- ray powder diffraction using an x-ray wavelength of 1.5406 A.
In one embodiment, there is provided crystalline 5-MeO-DMT hydrochloride, characterised by peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20±O.1°20 as measured by x- ray powder diffraction using an x-ray wavelength of 1.5406 A. In one embodiment, there is provided crystalline 5- MeO-DMT hydrochloride, characterised by peaks in an XRPD diffractogram at 9.2, 12.2, 13.7, 14.1, 15.0, 18.5, 19.0, 19.5, 21.2, 23.3, 23.9, 24.5, 25.1, 26.0, 26.9, 27.5, 28.3, 29.0, 30.9 and 31.1°20±O.1°20 as measured by x-ray powder
In one embodiment, there is provided crystalline 5-MeO-DMT hydrochloride, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figures 105, 106 or 107. In one embodiment, there is provided crystalline 5-MeO-DMT hydrochloride, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 105. In one embodiment, there is provided crystalline 5-MeO-DMT hydrochloride, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 106. In one embodiment, there is provided crystalline 5-MeO- DMT hydrochloride, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 107. In one embodiment, there is provided crystalline 5-MeO-DMT hydrochloride, characterised by one or more of:
Peaks in an XRPD diffractogram as previously or subsequently described;
An endothermic event in a DSC thermograph as previously or subsequently described;
An onset of decomposition in a TGA thermograph as previously or subsequently described;
A DVS isotherm profile as previously or subsequently described; and A crystalline structure as previously or subsequently described.
Example 50: Thermal Analysis of 5-MeO-DMT hydrochloride
Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) was performed on both lots at a standard heating rate of 10°C/Min from 30-400°C. In addition, DSC assessments of the solids were also conducted at 5, 20 and 40°C/Min heating rates. No significant differences in profile were observed between samples via DSC or TGA or via the variable DSC heating rates. An unstable DSC baseline is observed from 290°C onwards due to rapid decomposition of the material. Figure 108 shows a DSC and TGA thermograph of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP at 10°C/Min heating rate. Figure 109 shows DSC thermographs of 5-MeO-DMT hydrochloride, lot 20/20/126-FP at 5°C/Min (Black), 10°C/Min (Red), 20°C/Min (Blue) and 40°C/Min (Green) heating rates. Figure 110 shows a DSC and TGA thermograph of 5-MeO-DMT Hydrochloride, lot 20/45/006-FP at 10°C/Min heating rate. Figure 111 shows DSC thermographs of 5-MeO-DMT hydrochloride, lot 20/45/006-FP at 5°C/Min (Black), 10°C/Min (Red), 20°C/Min (Blue) and 40°C/Min (Green) heating rates. In one embodiment, there is provided a crystalline 5-MeO- DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, as substantially illustrated in Figure 108 or Figure 109. In one embodiment, there is provided a crystalline 5- MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 146°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 146°C as substantially illustrated in Figure 108 or Figure 109. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and a peak of between 142 and 148°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and a peak of between 142 and 148°C as substantially illustrated in Figure 108 or Figure 109. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.95°C and a peak of 146.74°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.95°C and a peak of 146.74°C as substantially illustrated in Figure 108 or Figure 109.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and an enthalpy of between - 113J/g and -123J/g. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and an enthalpy of between -113J/g and -123J/g as substantially illustrated in Figure 108 or Figure 109. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -113J/g and -123J/g. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -113J/g and -123J/g as substantially illustrated in Figure 108 or Figure 109. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.95°C, a peak of 146.74°C and an enthalpy of -118.29/g. In one embodiment, there is provided a crystalline 5- MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.95°C, a peak of 146.74°C and an enthalpy of -118.29/g as substantially illustrated in Figure 108 or Figure 109.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an onset of decomposition in a TGA thermograph of between 120 and 165°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 108. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C as substantially illustrated in Figure 108 or Figure 109; and an onset of decomposition in a TGA thermograph of between 120 and 165°C, as substantially illustrated in Figure 7.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C as substantially illustrated in Figure 108 or Figure 109; and an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 108.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -113J/g and -123J/g; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -113J/g and -123J/gas substantially illustrated in Figure 108 or Figure 109; and an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 108.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 145.95°C, a peak of 146.74°C and an enthalpy of -118.29J/g; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 145.95°C, a peak of 146.74°C and an enthalpy of -118.29J/g as substantially illustrated in Figure 108 or Figure 109; and an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 108.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, as substantially illustrated in Figure 110. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 146°C. In one embodiment, there is provided a crystalline 5- MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 146°C as substantially illustrated in Figure 110. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145°C as substantially illustrated in Figure 110.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and a peak of between 142 and 148°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and a peak of between 142 and 148°C as substantially illustrated in Figure 110. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.57°C and a peak of 146.22°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.57°C and a peak of 146.22°C as substantially illustrated in Figure 110. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and an enthalpy of between -115J/g and -125J/g. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and an enthalpy of between -115J/g and - 125J/g as substantially illustrated in Figure 110.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -115J/g and -125J/g. In one embodiment, there is provided a crystalline 5-MeO- DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -115J/g and -125J/g as substantially illustrated in Figure 110. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.57°C, a peak of 146.22°C and an enthalpy of -121.95J/g. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an endothermic event in a DSC thermograph having an onset temperature of 145.57°C, a peak of 146.22°C and an enthalpy of -121.95J/g as substantially illustrated in Figure 110.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an onset of decomposition in a TGA thermograph of between 120 and 165°C. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 110. In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C as substantially illustrated in Figure 110 or Figure 111; and an onset of decomposition in a TGA thermograph of between 120 and 165°C, as substantially illustrated in Figure 110.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C as substantially illustrated in Figure 110 or Figure 111; and an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 110.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -115J/g and -125J/g; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, a peak of between 142 and 148°C and an enthalpy of between -115J/g and -125J/gas substantially illustrated in Figure 110 or Figure 111; and an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 110.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 145.57°C, a peak of 146.22°C and an enthalpy of -121.95J/g; and an onset of decomposition in a TGA thermograph of between 120 and 165°C.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 145.57°C, a peak of 146.22°C and an enthalpy of -121.95J/g as substantially illustrated in Figure 110 or Figure 111; and an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 110.
Example 51: Dynamic Vapour Sorption (DVS) of 5-MeO-DMT hydrochloride
Sorption isotherms were obtained using a Hiden Isochema moisture sorption analyser (IGAsorp Systems Firmware V20.19.005 COM3) and operated by Isochema Hlsorp 2019 V4.02.0102. The sample was maintained at a constant temperature (25 QC) by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow of 250ml. min-1. The weight change of the sample was monitored as a function of humidity by a microbalance (accuracy +/- 0.005mg). The instrument was verified for relative humidity content by measuring three calibrated Rotronic salt solutions (10 - 50 - 88 %). A defined amount of sample was placed in a tared mesh stainless steel basket under ambient conditions. A typical experimental run consisted of three cycles (desorption, sorption, desorption, sorption, desorption and sorption) at a constant temperature (25°C) and 10 %RH intervals over a 0 - 90 %RH range (60 minutes for each humidity level). This type of experiment should demonstrate the ability of samples studied to absorb moisture (or not) over a set of well-determined humidity ranges.
The DVS isotherm of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP (Figure 112) was found to undergo significant moisture uptake upon the first sorption cycle from 70%RH. Approximately 23%w/w uptake is observed between 70- 80%RH, whereas less than 0.3%w/w moisture uptake from 0-70%RH was observed. A further 20%w/w moisture uptake is observed up to and when held at 90%RH before commencement of the second desorption cycle. Subsequent sorption and desorption cycles follow a similar profile with some observed hysteresis between operations that do not match the original desorption step. These return to ca. 6-9%w/w above the minimum mass recorded at 0%RH, which indicates significant retention of moisture. Upon completion of the DVS cycle, the input material was noted to have completed deliquesced. Following the DVS observations of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP, a modified DVS isotherm of lot 20/45/006-FP (the same crystalline version) was undertaken to examine material behaviour from 60%RH and above. A 2 cycle DVS with desorption beginning from 40-0%RH with sorption from 0- 60%RH in 10%RH intervals, followed by incremental 5%RH increases to 65, 70, 75, 80 and finally 85%RH. This is to obtain in-depth profiling of the material towards humidity at these elevated levels.
No significant moisture uptake/loss in first desorption-sorption profile between 0-70%RH was noted (Figure 113), followed by a ca. 0.46%w/w increase from 70-75%RH. A further ca. 7% uptake is observed from 75-80%RH, then ca. 40% from 80-85%w/w. Complete deliquescence of the solids was observed upon isolation of the material post DVS analysis, which has likely occurred above 80%RH. Despite the observed deliquescence above 80%RH, the solids demonstrate robustness between 0-75%RH and with adequate protection from moisture and conditional storage, this issue would likely be easily mitigated. In one embodiment, there is provided crystalline 5-MeO-DMT Hydrochloride, characterised by a DVS isotherm profile as substantially illustrated in Figure 112 or Figure 113.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, optionally a peak of between 142 and 148°C and optionally an enthalpy of between -115J/g and -125J/g; an onset of decomposition in a TGA thermograph of between 120 and 165°C; and a DVS isotherm profile as substantially illustrated in Figure 112 or Figure 113.
In one embodiment, there is provided a crystalline 5-MeO-DMT Hydrochloride, characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C, optionally a peak of between 142 and 148°C and optionally an enthalpy of between - 115J/g and -125J/g as substantially illustrated in Figure 110 or Figure 111; an onset of decomposition in a TGA thermograph of between 120 and 165°C as substantially illustrated in Figure 110; and a DVS isotherm profile as substantially illustrated in Figure 112 or Figure 113.
Example 52: Optical microscopy of 5-MeO-DMT hydrochloride
Optical microscopy examination was undertaken using an Olympus BX53M polarised light microscope and an Olympus SC50 digital video camera for image capture using imaging software Olympus Stream Basic, V2.4. The image scale bar was verified against an external graticule, 1.5/0.6/0.01 mm DIV, on a monthly basis. A small amount of each sample was placed onto a glass slide and dispersed as best as possible, using mineral dispersion oil if required. The samples were viewed with appropriate magnification and various images recorded. The microscopy of 5-MeO- DMT Hydrochloride, lots 20/20/126-FP (Figures 114-115) and 20/45/006-FP (Figures 116-117) do not differ significantly. Both consist of highly birefringent particulates with evidence of significant solid attrition of the particulates. A thin, columnar habit is, however, observed from individual crystallites that remain intact. There is also evidence of larger particulates that are made up of several individual crystallites that have accreted together during manufacture. Particle size of the main individual crystallites is estimated between ca. 10-50 pm, with some longer particulates up to 100 pm and a width of ca. 5-10 pm. A large quantity of smaller fragments of variable size and shape below 10 pm are noted, with several large solid accretions above 100 pm in diameter also present.
Two different hydrogel-forming MAPs (HF-MAPs) namely: 20% w/w Gantrez® S-97 + 7.5% w/w PEG 10,000 ('normal swelling') and 20% w/w Gantrez® S-97 + 7.5% w/w PEG 10,000 + 3% w/w Na2CO3 ('super swelling'). The swelling capacity, mechanical strength and needle insertion was assessed for all hydrogel-forming MAPs prior to in vitro testing. A schematic outlining the preparation of HF-MAPs is shown in Figure 124. Figure 125 shows HF-MAPs prepared when viewed using a light microscope.
The swelling capacity of each hydrogel formulation was assessed. The cross-linked HF-MAPs (NS & SS) were subjects for the swelling study. MAPs of each formulations (1 cm2) were weighed out in the dry state and recorded as mo (xerogels) at t = 0 (to). They were immersed in 40 mL of PBS at pH 7.4 for 24 hours at room temperature. MAPs were removed at predefined time points, where the excess surface water was carefully removed using filter paper prior to recording their masses as mt (hydrogels). Percentage of swelling was determined using the following Equation:
, , (mt — mO)
Swelling (%) = - x 100% mO
Figure 126 (A) shows a comparison of percentage swelling over 240 minutes with 20% w/w Gantrez8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCOa ('super swelling') and 20% w/w Gantrez8 S-97+ 7.5% w/w PEG 10,000 ('normal swelling'). Figure 126 (B) shows a comparison of percentage swelling over 24 hours with 20% w/w Gantrez8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCCh ('super swelling') and 20% w/w Gantrez8 S-97+ 7.5% w/w PEG 10,000 ('normal swelling'). The crosslinking reaction equations are shown below: (Crosslinking: reaction)
Figure 127 shows light microscope images of 20% w/w Gantrez8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCCh ('super swelling') before (A) and after (B) swelling in PBS.
Example 51: Mechanical characterisation of HF-MAPs.
MAPs were subject to insertion study using Parafilm M as an in vitro skin model. A 32 N force per patch was applied for 30 sec. This was chosen because it mimics mean human thumb force. The number of holes created in each Parafilm M layer were used to calculate the % of insertion using the following equation: number of holes observed
Insertion % = - - - - - ; - - - x 100% number of arrays in a MAP (121 array) Needle insertion was performed into 8 layers of Parafilm M using a 32 N force for 30 secs. This artificial membrane has been shown to be a suitable model for human skin. Again, there was no significant difference in needle insertion between the two formulations (p > 0.05), with ~ 100% penetration occurring in layers 1, 2 & 3. Therefore, both HF- MAPs can insert to a depth of 504-630 pm.
Figure 128 shows a Graphical representation of the number of Parafilm® M layers penetrated, and percentage holes created within each layer following a 32 N force applied for 30 s for three MAP design. Means ± S.D., n = 3.
MAPs were subjected to a compression study. MAPs were subjects to a compression study. MAPs were observed using a Leica light microscope, the heights of 20 MNs of each patch were manually measured (5 from each side). A 32 N force per patch was applied for 30 sec. This was chosen because it mimics mean human thumb force. MAPs were observed again and heights were measured following the compression test. Height reduction percentage was calculated using the following equation:
HO - Hl
Height reduction % = — — — x 100%
H 0
No significant difference in the height reduction percentage was observed when comparing normal swelling (NS) and super swelling (SS) formulations, suggesting that the addition of the modifying agent NazCOa did not have a significant effect on the mechanical properties of the microneedles (p < 0.05).
Figure 129 shows needle heights before and after compression of a 32 N force for 30 secs for the two MAP designs. Means + S.D., n = 3.
Example 52: Ex vivo permeation studies of 5-MeO-DMT HCI and benzoate usina Franz cells.
Excised dermatomed neonatal porcine skin (350 pm thick) was used to perform the permeation study. The release media was phosphate buffer solution (PBS) at pH 7.4. 5-MeO-DMT benzoate films contained ~ 8.5 mg drug, whereas 5-Meo-DMT HCI films contained ~ 11.2 mg (based on their weights). HF-MAPs formula containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000, and 3% NazCOa were used. Samples of 200 pL were taken over predefined time points (15 and 30 mins, 1,2,4, 6 and 24 hours) and were replaced with 200 pL fresh PBS solution.
Figure 130 shows a schematic representation of the Franz cells setup used for ex vivo permeation studies.
Approximately 2.72 ± 0.9 mg of the benzoate salt was delivered at 24 hr, representing 32 ± 9.9% from the original drug loading. On the other hand, 5.34 ± 0.31 mg of the HCI salt was delivered, representing 44.6 ± 4.4% of their initial drug loading. These results can be seen in Figure 1008.
Figure 131 shows (A) drug permeation %. Means + SD, n=3, (B) shows drug permeation quantity (mg). Means + SD, n=3.
Higher quantities (in mg) from the HCI salt was delivered into the Franz cell compared to the benzoate salt, however, no significant difference in the percentage delivered was seen due to the lower drug content of the benzoate films. This was expected and it is due to the relatively higher aqueous solubility of the HCI salt compared to the benzoate. Hence, more drug was loaded in films and more drug was delivered.
After the experiment was completed, drugs were extracted from MAPs, skin, and films residuals if any was present using the following steps:
Skin and HF-MAPs samples were initially cut into very small pieces, where 0.5 mL MeOH and 1 mL water were added, they were homogenised at 50 Hz for 20 mins using a Tissue Lyser LT to extract the drug from the samples. Samples were then diluted, centrifuged and analysed.
Some benzoate-containing films residuals were not completely dissolved at 24 hr, so they were dissolved in 15 mL of 2:1 water:MeOH, centrifuged, diluted properly and analysed.
From benzoate films, 2.72 ± 0.9 mg were delivered into the receiver compartment of FC, 1.31 ± 0.35 mg were recovered from HF-MAPs, 0.46 ± 0.26 from the skin and 3.44 ± 0.85 mg from films residuals. From HCI films, 5.34 ± 0.31 mg were detected in the receiver compartment of FC, 5.14 ± 0.81 mg were extracted from HF-MAPs and 0.62 ± 0.25 from the skin samples. The results can be seen in Figure 1009. Figure 132 shows (A) recovery % of both benzoate and HCI salts from each compartment at 24 hr. Means + SD, n=3, (B) shows quantity (mg) recovered from both benzoate and HCI salts from each compartment at 24 hr. Means + SD, n=3.
From the HCI-based films, more drug was recovered from HF-MAPs compared to the benzoate films. However, in benzoate films, there were some residuals of the film.
The total drug recovered from all compartments was studied. From benzoate films, 7.93 ± 0.62 mg were recovered, representing 92.17 ± 7.15% of initial drug loading. From HCI films, 11.03 ± 0.97 mg were recovered, representing 95.62 ± 6.98% of the initial drug loading.

Claims (1)

  1. Claims
    1. A method of synthesizing the benzoate salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with a base, prior to the addition of benzoic acid.
    2. The method of claim 1, wherein the benzoate salt is crystalline.
    3. The method of claim 1 or 2, wherein the method comprises the step of suspending the hydrochloride salt in a suspending organic solvent; wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
    4. The method of any preceding claim, wherein the benzoic acid is in solution in an organic solvent; wherein optionally the organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
    5. The method of any preceding claim, wherein the benzoic acid and the hydrochloride salt are present in substantially equal molar amounts.
    6. The method of any preceding claim, wherein the reaction with the benzoic acid takes place at an elevated temperature, optionally at a temperature between 40-65, 45-60, 50-55°C, or at/ near the boiling point of the resultant reaction mixture.
    7. The method of any preceding claim, wherein the reaction with the benzoic acid takes place at an elevated temperature, and the resultant reaction mixture is allowed to cool to room temperature or lower, is allowed to cool to below 10°C, is allowed to cool to below 5°C, or is allowed to cool to between 5 and 0°C.
    8. The method of any preceding claim, wherein the benzoate salt is filtered from the resultant reaction mixture.
    9. The method of claim 8, wherein the filtered benzoate salt is washed with a washing organic solvent; wherein optionally the washing organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
    10. The method of claim 8 or 9, wherein the benzoate salt is washed with cooled washing organic solvent, optionally the washing organic solvent is cooled to below room temperature, is cooled to below 10°C, is cooled to below 5°C, or cooled to between 5 and 0°C.
    11. The method of any one of claims 8 to 10, wherein the filtered benzoate salt is dried under vacuum.
    12. The method of any preceding claim, wherein the hydrochloride salt is base-treated with an aqueous basic solution, prior to the addition of benzoic acid.
    13. The method of claim 12, wherein the basic solution comprises an alkoxide, optionally the basic solution comprises sodium hydroxide, further optionally the basic solution is 5% aqueous sodium hydroxide.
    14. The method of claim 12 or 13, wherein the hydrochloride salt is suspended in the suspending organic solvent prior to being base-treated, wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
    15. The method of any one of claims 12 to 14, wherein the resultant based-treated reaction is partitioned with an extracting organic solvent to give an extract comprising the base-conditioned hydrochloride salt; wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
    16. The method of any one of claims 3 to 15, wherein the suspending organic solvent is isopropyl acetate (IPAc).
    17. The method of any one of claims 4 to 16, wherein the organic solvent is IPAc.
    18. The method of any one of claims 9 to 17, wherein the washing organic solvent is IPAc. The method of any one of claims 15 to 18, wherein the extracting organic solvent is IPAc. The method of any one of claims 15 to 19, wherein the organic phase is washed with water. The method of any one of claims 15 to 20, wherein the extract is reduced under vacuum to give a concentrate, optionally the extract is concentrated to approximately 8 volumes. The method of any one of claims 15 to 21, wherein the extract is azeotropically dried with one or more batches of fresh extracting organic solvent, optionally the extracting organic solvent is IPAc. The method of claim 1, wherein the method comprises the steps of:
    • combining 5-MeO-DMT hydrochloride salt and an organic solvent; optionally the organic solvent is IPAc
    • adding a basic solution to the combined 5-MeO-DMT hydrochloride salt and organic solvent; optionally the basic solution is aqueous 5% NaOH;
    • Partitioning;
    • washing the resulting organic phase with water;
    • drying the solvent; optionally azeotropically with IPAc
    • concentrating under vacuum;
    • adjusting the solvent temperature to between about 50-55°C;
    • adding a solution of benzoic acid in further organic solvent; optionally the further organic solvent is IPAc
    • adjusting the temperature to between about 0-5°C;
    • filtering and washing with cold solvent; optionally the cold solvent is IPAc
    • drying under vacuum to obtain the 5-MeO-DMT benzoate salt as a crystalline solid. The method of any one preceding claim, wherein the crystalline 5-MeO-DMT benzoate produced is characterised by one or more of:
    • peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20; and/or
    • endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C.; and/or
    • enthalpy in a DSC thermograph of between -130 and -140J/g; and/or
    • onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C. 5-MeO-DMT benzoate salt obtained by the method of any one of claims 1 to 23. An anti-inflammatory composition comprising 5-MeO-DMT benzoate. The anti-inflammatory composition of claim 26, wherein the 5-MeO-DMT benzoate is crystalline. The anti-inflammatory composition of claim 27, wherein the 5-MeO-DMT benzoate is characterised by peaks in an XRPD diffractogram (wavelength = 1.54056 A) at 17.5, 17.7 and 21.O°20±O.1°20. The anti-inflammatory composition of any one of claims 26 to 28 for use in a method of treatment, wherein administration of the composition to a patient in need thereof reduces the expression of the pro- inflammatory cytokine IL-lfJ. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of inflammation. The anti-inflammatory composition for use of claim 30, wherein the inflammation is chronic. The anti-inflammatory composition for use of claim 30, wherein the inflammation is acute. The anti-inflammatory composition for use of claim 30, wherein the method of treatment is a method of treatment of multiple sclerosis. The anti-inflammatory composition for use of claim 30, wherein the method of treatment is a method of treatment of post viral fatigue (PVF), such as long COVID. The anti-inflammatory composition for use of claim 30, wherein the method of treatment is a method of treatment of age-related macular degeneration, osteomyelitis, rheumatoid arthritis, diabetic retinopathy, retinitis pigmentosa or Cryopyrin-Associated Periodic Syndromes (CAPS). The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of acute, or chronic pain, including neuropathic pain. The anti-inflammatory composition for use of claim 36, wherein the method of treatment is a method of treatment of pain associated with or caused by one or more of :
    • Headache;
    • Trigeminal autonomic cephalalgia (TAC) (such as cluster headache, paroxysmal hemicranias, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) or long-lasting autonomic symptoms with hemicranias (LASH); or
    • Migraine. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of prophylactic treatment of migraine. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of fibromyalgia. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of, or a method of preventing the development of, traumatic brain injury. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of lessening the neurologic or psychiatric deficit after a traumatic brain injury and /or a cerebral ischemia related to a stroke, or global brain hypoxia, or an intracranial or epidural bleeding. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of a psychological/psychiatric disorder. The anti-inflammatory composition for use of claim 42, wherein psychological/psychiatric disorder is selected from one or more of:
    • Anxiety disorders;
    • Substance use disorders;
    • Post-traumatic stress disorder (PTSD)
    • Eating disorders;
    • Obsessive-compulsive disorders;
    • Body dysmorphic disorders;
    • Mood disorders;
    • Sleep disorders;
    • Personality disorders;
    • Psychotic disorders;
    • Impulse control disorders;
    • Dissociative disorders; • Cognitive disorders; or
    • Developmental disorders. The anti-inflammatory composition for use of claim 43, wherein the mood disorder is depression. The anti-inflammatory composition for use of claim 43, wherein the mood disorder is treatment-resistant depression. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of cancer. The anti-inflammatory composition for use of claim 46, wherein the method of treatment is a method of treatment of colon cancer, melanoma or lung cancer. The anti-inflammatory composition for use of claim 47, wherein the method of treatment is a method of treating malignant pleural mesothelioma. The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of a degenerative condition such as Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis (ALS). The anti-inflammatory composition for use of claim 29, wherein the method of treatment is a method of treatment of a seizure disorder, such as epilepsy. A microneedle array comprising a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable polymer composition, wherein the microneedle array further comprises 5-MeO-DMT. The microneedle array of claim 51, wherein the microneedle array further comprises an empathogen/entactogen, such as MDMA. The microneedle array of claim 52, wherein the empathogen/entactogen such as MDMA is coated on the outside of the tip of the microneedle and/or comprised within the polymer composition of the tip of the microneedle. The microneedle array of any one of claims 51 to 53, wherein the 5-MeO-DMT is comprised within the polymer composition of the microneedle array. The microneedle array of any one of claims 51 to 53, wherein the microneedle array further comprises a reservoir or matrix comprising 5-MeO-DMT or the microneedle array is in communication with a reservoir or matrix comprising 5-MeO-DMT. The microneedle array of any one of claims 51 to 55, wherein 5-MeO-DMT is present as the benzoate salt. The microneedle array of claim 56, wherein the 5-MeO-DMT benzoate is crystalline. The microneedle array of claim 56, wherein the 5-MeO-DMT benzoate is crystalline as characterised by peaks in an XRPD diffractogram (wavelength = 1.54056 A) at 17.5, 17.7 and 21.O°20±O.1°20. The microneedle array of any one of claims 51 to 55, wherein the 5-MeO-DMT is present as the hydrochloride salt. The microneedle array of claim 59, wherein the 5-MeO-DMT hydrochloride salt is crystalline as characterised by peaks in an XRPD diffractogram (wavelength = 1.54056 A) at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°20±O.1°20; The microneedle array of any one of claims 51 to 60, wherein the swellable polymer composition is a swellable hydrogel forming polymer composition. The microneedle array of claim 61, wherein the microneedles comprise one or more hydrogel-forming polymers containing one or more hydrophilic functional groups, such as polyvinylalcohol, amylopectin, carboxymethylcellulose (CMC)chitosan, poly(hydroxyethylmethacrylate) (polyHEMA), poly(acrylic acid), and poly(caprolactone), or a Gantrez ® -type polymer. The microneedle array of claim 61, wherein the microneedles comprise a Gantrez ® -type polymer. The microneedle array of any one of claims 51 to 63, wherein the polymer composition of the microneedles and/or the base element are cross-linked. The microneedle array of claim 64, wherein the cross-linking is physical or chemical or a combination of both. The microneedle array of claim 65, wherein the swellable hydrogel forming polymer composition is a Gantrez ® -type polymer cross-linked using a polyhydric alcohol. The microneedle array of any one of claims 51 to 66, wherein the microneedles of the microneedle array are l-3000pm in height. The microneedle array of any one of claims 51 to 67, wherein the microneedles of the microneedle array have a width (or, in the case of microneedles with substantially circular cross sections, a diameter) of 50 - 500 pm. The microneedle array of any one of claims 51 to 68, wherein the base element and the microneedles are comprised of the same material. The microneedle array of any one of claims 51 to 69, wherein the base element and the microneedles are comprised of different materials. The microneedle array of any one of claims 51 to 70, wherein the empathogen/entactogen is MDMA. A transdermal delivery device comprising a microneedle array as claimed in any one of claims 51 to 71. The transdermal delivery device of claim 72, wherein the movement of 5-MeO-DMT from the microneedle array into the skin is controlled iontopherically. The transdermal delivery device of claim 72 or claim 73 for use in a method of treatment. The transdermal delivery device of claim 74 for use in a method of treatment comprising the steps of:
    • Inducing a positive psychological state in a patient by administering the entactogen/empathogen, such as MDMA, component to the patient; and
    • administering the 5-MeO-DMT component to the patient. A prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises:
    • administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof;
    • monitoring the interaction of the patient with one or more components of the PDT via one or more electronic devices or inputs linked thereto;
    • assessing the interaction of the patient with the one or more components of the PDT;
    • determining the response of the patient to the administered dose of the 5-MeO-DMT benzoate salt based on the assessment of the interaction of the patient with the one or more components of the PDT; and
    138 • recommending a dose of the 5-MeO-DMT benzoate salt for further administration, or a cessation of further doses of the 5-MeO-DMT benzoate salt. The PDT for use in the method of claim 76, wherein the one or more components of the PDT comprise: guided meditation; breathing exercises; neuro/bio-feedback exercises; journaling; surveys/questionnaires; video and/or audio content; remote contact with one or more healthcare professionals (HCPs) and/or one or more peers who have experienced 5-MeO-DMT benzoate treatment (hereafter 'peers'); therapy tasks, such as the Values Card Sort Task; remote cognitive behavioral therapy (CBT); Al chat tools; and automated reminders and/or alerts. The PDT for use in the method of claim 76 or 77, wherein method additionally comprises the interaction of the patient with one or more components of the PDT occurs prior to administration of the dose of the 5-MeO-DMT benzoate salt, wherein administration of the dose of the 5-MeO-DMT benzoate only occurs if the interaction of the patient with one or more components of the PDT indicates the patient is likely to respond favourably to such administration. The PDT for use in the method of any one of claims 76 to 78, wherein the patient interacts with one or more components of the PDT via a dedicated application (app) present, or hosted, on one or more electronic devices. The PDT for use in the method of claim 79, wherein the app records data regarding the interaction of the patient with one or more of the:
    • guided meditation;
    • breathing exercises;
    • journaling;
    • surveys/questionnaires;
    • video and/or audio content;
    • remote HCPs and/or one or more peers who have experienced 5-MeO-DMT benzoate treatment (hereafter 'peers');
    • therapy tasks;
    • remote CBT;
    • Al chat tools; and
    • automated reminders and/or alerts and wherein the data is for use in determining the response of the patient to the administered dose of the 5-MeO-DMT benzoate salt, and/or for recommending a dose of the 5-MeO-DMT benzoate salt for further administration, or a cessation of further doses of the 5-MeO-DMT benzoate salt. The PDT for use in the method of claim 79 or 80, wherein the app records data regarding the interaction of the patient with one or more of:
    • human electronic device interaction patterns (e.g. screen touches);
    • patient movement (e.g. accelerometer and/or gyroscope data and/or GPS location data and/or Wi-Fi network interaction data);
    • patient physiology (e.g. heart rate and/or respiratory rate and/or galvanic skin response and/or blood pressure and/or temperature data and/or EEG data);
    • patient eye movement and blinking patterns;
    • patient facial movement patterns;
    • patient sleep patterns (e.g. frequency and/or duration and/or quality, as derived from electronic device usage patterns, actigraphy etc.);
    • patient communication patterns (e.g. messaging data and/or voice call data and/or voice over internet protocol [VoIP] data and/or contacts communicated with data
    139 and/or duration of inbound and outbound call data and/or instant messaging data); and/or
    • app usage data (e.g. number of app opens and/or duration of app usage and/or type of app usage). The PDT for use in the method of claims 76 to 81, wherein:
    • determining the response of the patient; and/or
    • recommending a dose of the 5-MeO-DMT benzoate salt; is done remotely by, or with the input from, one or more HCPs. The PDT for use in the method of claims 76 to 82, wherein the:
    • determining the response of the patient; and/or
    • recommending a dose of the 5-MeO-DMT benzoate salt; is done remotely by, or with input from, one or more algorithms. The PDT for use in the method of claims 76 to 83, wherein if it is determined that there is no, or little, beneficial response of the patient, then:
    • a treatment change is initiated to the dose of the 5-MeO-DMT benzoate salt; and/or
    • a treatment change is initiated to the one or more components of the PDT. The PDT for use in the method of claim 84, wherein the treatment change is initiated by, or made with the input from, one or more HCPs. The PDT for use in the method of claim 84 or 85, wherein the treatment change is initiated by, or made with the input from, one or more algorithms. The PDT for use in the method any one of claims 84 to 86, wherein the treatment change comprises a change in one or more of:
    • dose of the 5-MeO-DMT benzoate salt;
    • frequency of administration of the 5-MeO-DMT benzoate salt;
    • form of administration of the 5-MeO-DMT benzoate salt; and
    • components of the PDT. The PDT for use in the method of claim 87, wherein the change in the one or more components of the PDT is selected from a change in one or more of:
    • guided meditation;
    • breathing exercises;
    • neuro/bio-feedback exercises;
    • journaling;
    • surveys/questionnaires;
    • video and/or audio content;
    • remote contact with one or more HCPs) and/or one or more peers who have experienced 5-MeO-DMT benzoate treatment (hereafter 'peers');
    • therapy tasks, such as the Values Card Sort Task;
    • remote cognitive behavioral therapy (CBT);
    • Al chat tools; and
    • automated reminders and/or alerts. The PDT for use in the method of claims 76 to 88, wherein the one or more electronic devices are selected from:
    140 • smart device;
    • smartphone;
    • smartwatch;
    • smart glasses;
    • smart ring;
    • smart patch;
    • home hub smart device (e.g. Amazon Alexa™);
    • fitness tracker;
    • personal computer;
    • tablet (e.g. iPad™); and/or
    • EEG monitor.
    The PDT for use in the method of claims 76 to 89, wherein the one or more electronic devices records and transmits data associated with the patient and/or their interactions with one or more components of the PDT to a third party, optionally the third party is one or more HCPs. The PDT for use in the method of claim 90, wherein based on the transmitted data, the third party who is optionally one or more HCPs, initiates
    • a treatment change to the dose of the 5-MeO-DMT benzoate salt, and/or
    • a treatment change to the one or more components of the PDT. The PDT for use in the method of any one of claims 76 to 91, wherein the dosage amount of the dose of the 5-MeO-DMT benzoate salt is 1 to lOOmg. The PDT for use in the method of any one of claims 76 to 92, wherein the 5-MeO-DMT benzoate salt is formulated in an intranasal composition at a concentration of 70-140mg/ml and wherein the dose of the 5-MeO-DMT benzoate salt is administered to the patient via an intranasal route. The PDT for use in the method of any one of claims 76 to 93, wherein the 5-MeO-DMT benzoate salt is administered to the patient in the presence of a HCP in a dedicated treatment room, and optionally wherein the patient is sat down. The PDT for use in the method of any one of claims 76 to 94, wherein the method of treatment is for the treatment of any one of:
    • conditions caused by dysfunctions of the central nervous system;
    • conditions caused by dysfunctions of the peripheral nervous system;
    • conditions benefiting from sleep regulation (such as insomnia);
    • conditions benefiting from analgesics (such as chronic pain);
    • migraines;
    • trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA));
    • conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia);
    • conditions benefiting from anti-inflammatory treatment;
    • depression;
    • treatment-resistant depression;
    • anxiety;
    • substance use disorder;
    • addictive disorder;
    • gambling disorder;
    • eating disorders;
    141 mood disorders, such as PTSD; obsessive-compulsive disorders; and body dysmorphic disorders. The PDT for use in the method of any one of claims 76 to 95, wherein the method of treatment is for the treatment of treatment-resistant depression. The PDT for use in the method of claim 96, wherein the method comprises:
    • administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof;
    • wherein the dose is administered intranasally in a dosage amount of 1 to 50mg;
    • monitoring the interaction of the patient with one or more components of the PDT via one or more electronic devices or inputs linked thereto;
    • wherein the electronic device is a smart phone and the one or more components comprise, or consists of, remote CBT, guided meditation, breathing exercises, therapy tasks, surveys/questionnaires, remote contact with HCPs and journals;
    • assessing the interaction of the patient with the one or more components of the PDT;
    • determining the response of the patient to the administered dose of the 5-MeO-DMT benzoate salt based on the assessment of the interaction of the patient with the one or more components of the PDT; and
    • recommending a dose of the 5-MeO-DMT benzoate salt for further administration, or a cessation of further doses of the 5-MeO-DMT benzoate salt, wherein determining the response of the patient and/or recommending a dose of the 5-MeO-DMT benzoate salt is done remotely by, or with the input from, one or more HCPs and/or one or more algorithms; wherein if it is determined that there is no, or little, beneficial response of the patient, then
    • a treatment change is initiated to the dose of the 5-MeO-DMT benzoate salt, and/or
    • a treatment change is initiated to the one or more components of the PDT; wherein optionally, the treatment change comprises an increase in one or more of:
    • the dosage amount of the 5-MeO-DMT benzoate salt;
    • frequency of administration of the 5-MeO-DMT benzoate salt; and
    • frequency of remote CBT. The PDT for use in the method of any one of claims 76 to 97, wherein the 5-MeO-DMT benzoate salt is crystalline and characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. A prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof, wherein the method of treatment is for the treatment of any one of:
    • conditions caused by dysfunctions of the central nervous system;
    • conditions caused by dysfunctions of the peripheral nervous system;
    • conditions benefiting from sleep regulation (such as insomnia);
    • conditions benefiting from analgesics (such as chronic pain);
    • migraines;
    • trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA));
    142 • conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia);
    • conditions benefiting from anti-inflammatory treatment;
    • depression;
    • treatment-resistant depression;
    • anxiety;
    • substance use disorder;
    • addictive disorder;
    • gambling disorder;
    • eating disorders;
    • obsessive-compulsive disorders; or
    • body dysmorphic disorders. A prescription digital therapeutic (PDT) for use in a method of medical treatment, wherein the method comprises administering a dose of 5-MeO-DMT benzoate salt to a patient in need thereof, wherein the method of treatment is for the treatment of treatment-resistant depression. 5-MeO-DMT benzoate for use in a method of treatment of a psychiatric neurological disorder, the method comprising administering a dose of 5-MeO-DMT benzoate to a patient in need thereof, wherein the brain activity of the patient is monitored using electroencephalography (EEG). The 5-MeO-DMT benzoate for use of claim 101, wherein EEG is monitored to indicate the onset or presence of ego-dissolution or altered consciousness. The 5-MeO-DMT benzoate for use of claim 101 or 102, wherein the onset or presence of ego-dissolution or altered consciousness is characterised by a characteristic EEG pattern. The 5-MeO-DMT benzoate for use of any one of claims 101 to 103, wherein the characteristic EEG pattern is pathognomonic and/or indicative of a 5-MeO-DMT therapeutic response. The 5-MeO-DMT benzoate for use of any one of claims 101 to 104, wherein the EEG pattern is selected from one or more of: location-specific (e.g. prefrontal, and frontal) alterations; decreases in total spectral power in alpha and/or beta bands; marked increases in spontaneous signal diversity; emergence of theta and/or delta oscillations. The 5-MeO-DMT benzoate for use of any one of claims 101 to 105, wherein a subsequent dose of 5-MeO- DMT benzoate is administered to the patient, in the case where the onset or presence of ego-dissolution or altered consciousness is not indicated by the EEG in an assessment window following a prior dose of 5- MeO-DMT benzoate. The 5-MeO-DMT benzoate for use of any one of claims 101 to 106, wherein a subsequent dose of 5-MeO- DMT benzoate is not administered to the patient, in the case where the onset or presence of egodissolution or altered consciousness is indicated by the EEG in an assessment window, following a prior dose of 5-MeO-DMT benzoate. The 5-MeO-DMT benzoate for use of any one of claims 101 to 107, wherein a subsequent dose of 5-MeO- DMT benzoate is administered to the patient, in the case where the ending of ego-dissolution or altered consciousness is indicated by the EEG in an assessment window following a prior dose of 5-MeO-DMT benzoate. The 5-MeO-DMT benzoate for use of any one of claims 101 to 108, wherein a subsequent dose of 5-MeO- DMT benzoate is not administered to the patient, in the case where a session assessment window has expired following a prior, or first, dose of 5-MeO-DMT benzoate.
    143 The 5-MeO-DMT benzoate for use of any one of claims 101 to 109, wherein the monitored brain activity of the patient is assessed with reference to a database of EEG measurements taken from patients undergoing, and/or who have undergone, 5-MeO-DMT benzoate therapy. The 5-MeO-DMT benzoate for use of any one of claims 101 to 110, wherein the 5-MeO-DMT benzoate is administered via an intranasal route. The 5-MeO-DMT benzoate for use of any one of claims 101 to 111, wherein the 5-MeO-DMT benzoate is administered via a transdermal route via a microneedle patch, or a transdermal patch pump. The 5-MeO-DMT benzoate for use of claim 112, wherein the microneedle patch is removed, or the patch pump infusion is stopped, in the case where the onset or presence of ego-dissolution or altered consciousness is indicated by the EEG in an assessment window. The 5-MeO-DMT benzoate for use of any one of claims 101 to 113, wherein the dose or dosages of 5- MeO-DMT benzoate is administered via a continuous s/c infusion or a transdermal patch pump. The 5-MeO-DMT benzoate for use of claim 114 wherein the dose or dosages of 5-MeO-DMT benzoate is administered so as to maintain a state of ego-dissolution or altered consciousness for a desired time window of time. The 5-MeO-DMT benzoate for use of any one of claims 101 to 115, wherein prior to administration of the 5-MeO-DMT benzoate to the patient, the patient takes part in a dose finding screening exercise, wherein the brain activity of the patient is monitored using EEG during the administration of increasing dosages of 5-MeO-DMT benzoate, in order to select a suitable treatment dose. The 5-MeO-DMT benzoate for use of any one of claims 101 to 116, wherein the patient is monitored using an electroencephalography (EEG) headset which is connected to a app, smart phone device, tablet, computer device, or equivalent device, and in the case where the onset or presence of ego-dissolution or altered consciousness is indicated, a visual and/or audible alert is generated by the app, smart phone device, tablet, computer device, or equivalent device. The 5-MeO-DMT benzoate for use of claim 117, wherein the headset is connected to the app, smart phone device, tablet, computer device, or equivalent device via a wireless connection, e.g. via Bluetooth®. The 5-MeO-DMT benzoate for use of any one of claims 101 to 118, wherein the patient is monitored using an electroencephalography (EEG) headset and when the onset or presence of ego-dissolution or altered consciousness is indicated, a visual and/or audible alert is generated by the headset. The 5-MeO-DMT benzoate for use of any one of claims 101 to 119, wherein the brain activity (e.g. EEG data), of the patient is monitored by a computer algorithm. The 5-MeO-DMT benzoate for use of claim 120, wherein the onset of or presence ego-dissolution or altered consciousness is determined by the computer algorithm or is determined together with the authority of a supervising healthcare professional (HCP). The 5-MeO-DMT benzoate for use of any one of claims 101 to 121, wherein the 5-MeO-DMT benzoate is amorphous, or is crystalline and characterised by one or more of:
    • peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20;
    • peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1°20;
    • peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7,
    24.7 and 25.3°20±O.1°20; peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.1°20 using an x-ray wavelength of 1.5406 A;
    144 • an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C. The 5-MeO-DMT benzoate for use of any one of claims 101 to 122, wherein the treatment takes place in a dedicated therapy space in the presence of a supervising healthcare professional (HCP). The 5-MeO-DMT benzoate for use of claim 123, wherein the supervising HCP and the patient engage in psychotherapy, optionally such therapy is initiated following the indication that ego-dissolution is imminent, is occurring or has occurred. The 5-MeO-DMT benzoate for use of any one of claims 101 to 124, where the 5-MeO-DMT benzoate may be any salt of 5-MeO-DMT such as the chloride salt, or may be the freebase of 5-MeO-DMT.
    145
AU2022413759A 2021-12-13 2022-12-13 Benzoate salt of 5-methoxy-n,n-dimethyltryptamine Pending AU2022413759A1 (en)

Applications Claiming Priority (29)

Application Number Priority Date Filing Date Title
GB2118011.2 2021-12-13
GBGB2118007.0A GB202118007D0 (en) 2021-12-13 2021-12-13 Methods of treatment
GB2118006.2 2021-12-13
GBGB2118006.2A GB202118006D0 (en) 2021-12-13 2021-12-13 Methods of treatment
GBGB2118008.8A GB202118008D0 (en) 2021-12-13 2021-12-13 Combination Pharmaceutical composition
GB2118008.8 2021-12-13
GB2118005.4 2021-12-13
GB2118007.0 2021-12-13
GBGB2118011.2A GB202118011D0 (en) 2021-12-13 2021-12-13 Methods of treatment
GBGB2118005.4A GB202118005D0 (en) 2021-12-13 2021-12-13 Methods of synthesis
GB2118099.7 2021-12-14
GBGB2118095.5A GB202118095D0 (en) 2021-12-14 2021-12-14 Combination pharmaceutical composition
GBGB2118099.7A GB202118099D0 (en) 2021-12-14 2021-12-14 Methods of synthesis
GB2118095.5 2021-12-14
GB2118156.5 2021-12-15
GBGB2118156.5A GB202118156D0 (en) 2021-12-15 2021-12-15 Methods of synthesis
GB202118305 2021-12-16
GB2118293.6 2021-12-16
GB202118293 2021-12-16
GB2118295.1 2021-12-16
GB2118309.0 2021-12-16
GB2118305.8 2021-12-16
GB202118295 2021-12-16
GB202118309 2021-12-16
GB2212113.1 2022-08-19
GBGB2212113.1A GB202212113D0 (en) 2022-08-19 2022-08-19 Method of synthesis
GBGB2212117.2A GB202212117D0 (en) 2022-08-19 2022-08-19 Method of synthesis
GB2212117.2 2022-08-19
PCT/GB2022/053208 WO2023111544A2 (en) 2021-12-13 2022-12-13 Benzoate salt of 5-methoxy-n,n-dimethyltryptamine

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EP4499074A1 (en) * 2022-03-27 2025-02-05 GH Research Ireland Limited 5-meo-dtm for the treatment of bipolar disorder
US12264131B2 (en) * 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
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US12246005B2 (en) 2023-06-13 2025-03-11 Beckley Psytech Limited 5-methoxy-n,n-dimethyltryptamine (5-MeO-DMT) formulations
WO2025054397A1 (en) * 2023-09-08 2025-03-13 Atai Therapeutics, Inc. Parenteral formulations for n,n-dimethyltryptamine (dmt) and dmt analogs, methods of making, and methods of use thereof
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